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QSAR and Chemoinformatics Tools for Modeling

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Informatics".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 100047

Special Issue Editor

Prof. Dr. Roberto Todeschini

E-Mail Website
Guest Editor
Milano Chemometrics and QSAR Research Group, Department of Environmental Sciences, University of Milano-Bicocca, 20126 Milano, Italy
Interests: chemometric; QSAR/QSPR; multi-criteria decision making; molecular descriptors; software development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the past decade, quantitative structure–activity relationships (QSARs) have become a well-established field of scientific research, a field where many different mathematical tools are applied to detect predictive relationships between molecular structure and pharmacological activities, toxicological/ecotoxicological properties, and adverse effects of molecules on human health.
In the proposed Special Issue, the main idea is not only to present QSAR results on new datasets/modelling campaigns, but also to compare different chemometric and chemoinformatic tools on benchmark data sets, especially including (together with the classical regression and classification methods) read-across approaches, ranking models, machine learning, and deep learning methods.
Authors are also invited to pay attention to the concept of the applicability domain of the models, their prediction ability, and models obtained by data fusion and consensus approaches.
Molecular applications aimed to model endocrine disruptors effects, carcinogenicity, and mutagenicity as well as studies on omics data will be particularly appreciated.

Prof. Dr. Roberto Todeschini
Guest Editor

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Keywords

  • QSAR
  • QSPR
  • chemometrics
  • chemoinformatics
  • machine learning
  • applicability domain
  • regression models
  • classification models
  • ranking models
  • consensus models
  • molecular descriptors
  • omics data
  • endocrine disruptors
  • carcinogenicity
  • mutagenicity

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Published Papers (20 papers)

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Research

27 pages, 2021 KiB  
Article
Use of QSAR Global Models and Molecular Docking for Developing New Inhibitors of c-src Tyrosine Kinase
by Robert Ancuceanu, Bogdan Tamba, Cristina Silvia Stoicescu and Mihaela Dinu
Int. J. Mol. Sci. 2020, 21(1), 19; https://doi.org/10.3390/ijms21010019 - 18 Dec 2019
Cited by 12 | Viewed by 4988
Abstract
A prototype of a family of at least nine members, cellular Src tyrosine kinase is a therapeutically interesting target because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative [...] Read more.
A prototype of a family of at least nine members, cellular Src tyrosine kinase is a therapeutically interesting target because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We explored the use of global quantitative structure-activity relationship (QSAR) models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a dataset of 1038 compounds from ChEMBL database, we developed over 350 QSAR classification models. A total of 49 models with reasonably good performance were selected and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over 100,000 compounds. A total of 744 compounds were predicted by at least 50% of the QSAR models as active, 147 compounds were within the applicability domain and predicted by at least 75% of the models to be active. The latter 147 compounds were submitted to molecular ligand docking using AutoDock Vina and LeDock, and 89 were predicted to be active based on the energy of binding. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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13 pages, 1951 KiB  
Article
QSAR Models for Predicting Five Levels of Cellular Accumulation of Lysosomotropic Macrocycles
by Ulf Norinder and Vesna Munic Kos
Int. J. Mol. Sci. 2019, 20(23), 5938; https://doi.org/10.3390/ijms20235938 - 26 Nov 2019
Cited by 7 | Viewed by 3034
Abstract
Drugs that accumulate in lysosomes reach very high tissue concentrations, which is evident in the high volume of distribution and often lower clearance of these compounds. Such a pharmacokinetic profile is beneficial for indications where high tissue penetration and a less frequent dosing [...] Read more.
Drugs that accumulate in lysosomes reach very high tissue concentrations, which is evident in the high volume of distribution and often lower clearance of these compounds. Such a pharmacokinetic profile is beneficial for indications where high tissue penetration and a less frequent dosing regime is required. Here, we show how the level of lysosomotropic accumulation in cells can be predicted solely from molecular structure. To develop quantitative structure–activity relationship (QSAR) models, we used cellular accumulation data for 69 lysosomotropic macrocycles, the pharmaceutical class for which this type of prediction model is extremely valuable due to the importance of cellular accumulation for their anti-infective and anti-inflammatory applications as well as due to the fact that they are extremely difficult to model by computational methods because of their large size (Mw > 500). For the first time, we show that five levels of intracellular lysosomotropic accumulation (as measured by liquid chromatography coupled to tandem mass spectrometry—LC-MS/MS), from low/no to extremely high, can be predicted with 60% balanced accuracy solely from the compound’s structure. Although largely built on macrocycles, the eight non-macrocyclic compounds that were added to the set were found to be well incorporated by the models, indicating their possible broader application. By uncovering the link between the molecular structure and cellular accumulation as the key process in tissue distribution of lysosomotropic compounds, these models are applicable for directing the drug discovery process and prioritizing the compounds for synthesis with fine-tuned accumulation properties, according to the desired pharmacokinetic profile. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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25 pages, 5674 KiB  
Article
Meta-iAVP: A Sequence-Based Meta-Predictor for Improving the Prediction of Antiviral Peptides Using Effective Feature Representation
by Nalini Schaduangrat, Chanin Nantasenamat, Virapong Prachayasittikul and Watshara Shoombuatong
Int. J. Mol. Sci. 2019, 20(22), 5743; https://doi.org/10.3390/ijms20225743 - 15 Nov 2019
Cited by 103 | Viewed by 8290
Abstract
In spite of the large-scale production and widespread distribution of vaccines and antiviral drugs, viruses remain a prominent human disease. Recently, the discovery of antiviral peptides (AVPs) has become an influential antiviral agent due to their extraordinary advantages. With the avalanche of newly-found [...] Read more.
In spite of the large-scale production and widespread distribution of vaccines and antiviral drugs, viruses remain a prominent human disease. Recently, the discovery of antiviral peptides (AVPs) has become an influential antiviral agent due to their extraordinary advantages. With the avalanche of newly-found peptide sequences in the post-genomic era, there is a great demand to develop a sequence-based predictor for timely identifying AVPs as this information is very useful for both basic research and drug development. In this study, we propose a novel sequence-based meta-predictor with an effective feature representation, called Meta-iAVP, for the accurate prediction of AVPs from given peptide sequences. Herein, the effective feature representation was extracted from a set of prediction scores derived from various machine learning algorithms and types of features. To the best of our knowledge, the model proposed herein represents the first meta-based approach for the prediction of AVPs. An overall accuracy and Matthews correlation coefficient of 95.20% and 0.90, respectively, was achieved from the independent test set on an objective benchmark dataset. Comparative analysis suggested that Meta-iAVP was superior to that of existing methods and therefore represents a useful tool for AVP prediction. Finally, in an effort to facilitate high-throughput prediction of AVPs, the model was deployed as the Meta-iAVP web server and is made freely available online at http://codes.bio/meta-iavp/ where users can submit query peptide sequences for determining the likelihood of whether or not these peptides are AVPs. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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13 pages, 271 KiB  
Article
Alignment-Free Method to Predict Enzyme Classes and Subclasses
by Riccardo Concu and M. Natália D. S. Cordeiro
Int. J. Mol. Sci. 2019, 20(21), 5389; https://doi.org/10.3390/ijms20215389 - 29 Oct 2019
Cited by 22 | Viewed by 4917
Abstract
The Enzyme Classification (EC) number is a numerical classification scheme for enzymes, established using the chemical reactions they catalyze. This classification is based on the recommendation of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. Six enzyme classes were [...] Read more.
The Enzyme Classification (EC) number is a numerical classification scheme for enzymes, established using the chemical reactions they catalyze. This classification is based on the recommendation of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. Six enzyme classes were recognised in the first Enzyme Classification and Nomenclature List, reported by the International Union of Biochemistry in 1961. However, a new enzyme group was recently added as the six existing EC classes could not describe enzymes involved in the movement of ions or molecules across membranes. Such enzymes are now classified in the new EC class of translocases (EC 7). Several computational methods have been developed in order to predict the EC number. However, due to this new change, all such methods are now outdated and need updating. In this work, we developed a new multi-task quantitative structure–activity relationship (QSAR) method aimed at predicting all 7 EC classes and subclasses. In so doing, we developed an alignment-free model based on artificial neural networks that proved to be very successful. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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29 pages, 4248 KiB  
Article
SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors
by Andrzej Bak, Hana Pizova, Violetta Kozik, Katarina Vorcakova, Jiri Kos, Jakub Treml, Klara Odehnalova, Michal Oravec, Ales Imramovsky, Pavel Bobal, Adam Smolinski, Zdeněk Trávníček and Josef Jampilek
Int. J. Mol. Sci. 2019, 20(21), 5385; https://doi.org/10.3390/ijms20215385 - 29 Oct 2019
Cited by 12 | Viewed by 4160
Abstract
A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron [...] Read more.
A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure–activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity–activity landscape index for BChE inhibitory response values. The ‘indirect’ ligand-based and ‘direct’ protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an ‘average’ 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII). Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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17 pages, 1069 KiB  
Article
Prediction Model with High-Performance Constitutive Androstane Receptor (CAR) Using DeepSnap-Deep Learning Approach from the Tox21 10K Compound Library
by Yasunari Matsuzaka and Yoshihiro Uesawa
Int. J. Mol. Sci. 2019, 20(19), 4855; https://doi.org/10.3390/ijms20194855 - 30 Sep 2019
Cited by 28 | Viewed by 4511
Abstract
The constitutive androstane receptor (CAR) plays pivotal roles in drug-induced liver injury through the transcriptional regulation of drug-metabolizing enzymes and transporters. Thus, identifying regulatory factors for CAR activation is important for understanding its mechanisms. Numerous studies conducted previously on CAR activation and its [...] Read more.
The constitutive androstane receptor (CAR) plays pivotal roles in drug-induced liver injury through the transcriptional regulation of drug-metabolizing enzymes and transporters. Thus, identifying regulatory factors for CAR activation is important for understanding its mechanisms. Numerous studies conducted previously on CAR activation and its toxicity focused on in vivo or in vitro analyses, which are expensive, time consuming, and require many animals. We developed a computational model that predicts agonists for the CAR using the Toxicology in the 21st Century 10k library. Additionally, we evaluate the prediction performance of novel deep learning (DL)-based quantitative structure-activity relationship analysis called the DeepSnap-DL approach, which is a procedure of generating an omnidirectional snapshot portraying three-dimensional (3D) structures of chemical compounds. The CAR prediction model, which applies a 3D structure generator tool, called CORINA-generated and -optimized chemical structures, in the DeepSnap-DL demonstrated better performance than the existing methods using molecular descriptors. These results indicate that high performance in the prediction model using the DeepSnap-DL approach may be important to prepare suitable 3D chemical structures as input data and to enable the identification of modulators of the CAR. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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23 pages, 4278 KiB  
Article
Skin Doctor: Machine Learning Models for Skin Sensitization Prediction that Provide Estimates and Indicators of Prediction Reliability
by Anke Wilm, Conrad Stork, Christoph Bauer, Andreas Schepky, Jochen Kühnl and Johannes Kirchmair
Int. J. Mol. Sci. 2019, 20(19), 4833; https://doi.org/10.3390/ijms20194833 - 28 Sep 2019
Cited by 18 | Viewed by 4593
Abstract
The ability to predict the skin sensitization potential of small organic molecules is of high importance to the development and safe application of cosmetics, drugs and pesticides. One of the most widely accepted methods for predicting this hazard is the local lymph node [...] Read more.
The ability to predict the skin sensitization potential of small organic molecules is of high importance to the development and safe application of cosmetics, drugs and pesticides. One of the most widely accepted methods for predicting this hazard is the local lymph node assay (LLNA). The goal of this work was to develop in silico models for the prediction of the skin sensitization potential of small molecules that go beyond the state of the art, with larger LLNA data sets and, most importantly, a robust and intuitive definition of the applicability domain, paired with additional indicators of the reliability of predictions. We explored a large variety of molecular descriptors and fingerprints in combination with random forest and support vector machine classifiers. The most suitable models were tested on holdout data, on which they yielded competitive performance (Matthews correlation coefficients up to 0.52; accuracies up to 0.76; areas under the receiver operating characteristic curves up to 0.83). The most favorable models are available via a public web service that, in addition to predictions, provides assessments of the applicability domain and indicators of the reliability of the individual predictions. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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32 pages, 13546 KiB  
Article
Structure-Based Design and in Silico Screening of Virtual Combinatorial Library of Benzamides Inhibiting 2-trans Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Predicted Pharmacokinetic Profiles
by Koffi Charles Kouman, Melalie Keita, Raymond Kre N’Guessan, Luc Calvin Owono Owono, Eugene Megnassan, Vladimir Frecer and Stanislav Miertus
Int. J. Mol. Sci. 2019, 20(19), 4730; https://doi.org/10.3390/ijms20194730 - 24 Sep 2019
Cited by 4 | Viewed by 4100
Abstract
Background: During the previous decade a new class of benzamide-based inhibitors of 2-trans enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (Mt) with unusual binding mode have emerged. Here we report in silico design and evaluation of novel benzamide InhA-Mt inhibitors with favorable [...] Read more.
Background: During the previous decade a new class of benzamide-based inhibitors of 2-trans enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (Mt) with unusual binding mode have emerged. Here we report in silico design and evaluation of novel benzamide InhA-Mt inhibitors with favorable predicted pharmacokinetic profiles. Methods: By using in situ modifications of the crystal structure of N-benzyl-4-((heteroaryl)methyl) benzamide (BHMB)-InhA complex (PDB entry 4QXM), 3D models of InhA-BHMBx complexes were prepared for a training set of 19 BHMBs with experimentally determined inhibitory potencies (half-maximal inhibitory concentrations IC50exp). In the search for active conformation of the BHMB1-19, linear QSAR model was prepared, which correlated computed gas phase enthalpies of formation (∆∆HMM) of InhA-BHMBx complexes with the IC50exp. Further, taking into account the solvent effect and entropy changes upon ligand, binding resulted in a superior QSAR model correlating computed complexation Gibbs free energies (∆∆Gcom). The successive pharmacophore model (PH4) generated from the active conformations of BHMBs served as a virtual screening tool of novel analogs included in a virtual combinatorial library (VCL) of compounds containing benzamide scaffolds. The VCL filtered by Lipinski’s rule-of-five was screened by the PH4 model to identify new BHMB analogs. Results: Gas phase QSAR model: −log10(IC50exp) = pIC50exp = −0.2465 × ∆∆HMM + 7.95503, R2 = 0.94; superior aqueous phase QSAR model: pIC50exp = −0.2370 × ∆∆Gcom + 7.8783, R2 = 0.97 and PH4 pharmacophore model: p IC 50 exp = 1.0013 × p IC 50 exp − 0.0085, R2 = 0.95. The VCL of more than 114 thousand BHMBs was filtered down to 73,565 analogs Lipinski’s rule. The five-point PH4 screening retained 90 new and potent BHMBs with predicted inhibitory potencies IC50pre up to 65 times lower than that of BHMB1 (IC50exp = 20 nM). Predicted pharmacokinetic profile of the new analogs showed enhanced cell membrane permeability and high human oral absorption compared to current anti-tuberculotics. Conclusions: Combined use of QSAR models that considered binding of the BHMBs to InhA, pharmacophore model, and ADME properties helped to recognize bound active conformation of the benzamide inhibitors, permitted in silico screening of VCL of compounds sharing benzamide scaffold and identification of new analogs with predicted high inhibitory potencies and favorable pharmacokinetic profiles. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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10 pages, 1463 KiB  
Article
Improvement of Epitope Prediction Using Peptide Sequence Descriptors and Machine Learning
by Cristian R. Munteanu, Marcos Gestal, Yunuen G. Martínez-Acevedo, Nieves Pedreira, Alejandro Pazos and Julián Dorado
Int. J. Mol. Sci. 2019, 20(18), 4362; https://doi.org/10.3390/ijms20184362 - 5 Sep 2019
Cited by 6 | Viewed by 3992
Abstract
In this work, we improved a previous model used for the prediction of proteomes as new B-cell epitopes in vaccine design. The predicted epitope activity of a queried peptide is based on its sequence, a known reference epitope sequence under specific experimental conditions. [...] Read more.
In this work, we improved a previous model used for the prediction of proteomes as new B-cell epitopes in vaccine design. The predicted epitope activity of a queried peptide is based on its sequence, a known reference epitope sequence under specific experimental conditions. The peptide sequences were transformed into molecular descriptors of sequence recurrence networks and were mixed under experimental conditions. The new models were generated using 709,100 instances of pair descriptors for query and reference peptide sequences. Using perturbations of the initial descriptors under sequence or assay conditions, 10 transformed features were used as inputs for seven Machine Learning methods. The best model was obtained with random forest classifiers with an Area Under the Receiver Operating Characteristics (AUROC) of 0.981 ± 0.0005 for the external validation series (five-fold cross-validation). The database included information about 83,683 peptides sequences, 1448 epitope organisms, 323 host organisms, 15 types of in vivo processes, 28 experimental techniques, and 505 adjuvant additives. The current model could improve the in silico predictions of epitopes for vaccine design. The script and results are available as a free repository. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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17 pages, 709 KiB  
Article
Development of Multi-Target Chemometric Models for the Inhibition of Class I PI3K Enzyme Isoforms: A Case Study Using QSAR-Co Tool
by Amit Kumar Halder and M. Natália Dias Soeiro Cordeiro
Int. J. Mol. Sci. 2019, 20(17), 4191; https://doi.org/10.3390/ijms20174191 - 27 Aug 2019
Cited by 21 | Viewed by 5652
Abstract
The present work aims at establishing multi-target chemometric models using the recently launched quantitative structure–activity relationship (QSAR)-Co tool for predicting the activity of inhibitor compounds against different isoforms of phosphoinositide 3-kinase (PI3K) under various experimental conditions. The inhibitors of class I phosphoinositide 3-kinase [...] Read more.
The present work aims at establishing multi-target chemometric models using the recently launched quantitative structure–activity relationship (QSAR)-Co tool for predicting the activity of inhibitor compounds against different isoforms of phosphoinositide 3-kinase (PI3K) under various experimental conditions. The inhibitors of class I phosphoinositide 3-kinase (PI3K) isoforms have emerged as potential therapeutic agents for the treatment of various disorders, especially cancer. The cell-based enzyme inhibition assay results of PI3K inhibitors were curated from the CHEMBL database. Factors such as the nature and mutation of cell lines that may significantly alter the assay outcomes were considered as important experimental elements for mt-QSAR model development. The models, in turn, were developed using two machine learning techniques as implemented in QSAR-Co: linear discriminant analysis (LDA) and random forest (RF). Both techniques led to models with high accuracy (ca. 90%). Several molecular fragments were extracted from the current dataset, and their quantitative contributions to the inhibitory activity against all the proteins and experimental conditions under study were calculated. This case study also demonstrates the utility of QSAR-Co tool in solving multi-factorial and complex chemometric problems. Additionally, the combination of different in silico methods employed in this work can serve as a valuable guideline to speed up early discovery of PI3K inhibitors. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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24 pages, 3272 KiB  
Article
In Silico Prediction of PAMPA Effective Permeability Using a Two-QSAR Approach
by Cheng-Ting Chi, Ming-Han Lee, Ching-Feng Weng and Max K. Leong
Int. J. Mol. Sci. 2019, 20(13), 3170; https://doi.org/10.3390/ijms20133170 - 28 Jun 2019
Cited by 40 | Viewed by 6186
Abstract
Oral administration is the preferred and predominant route of choice for medication. As such, drug absorption is one of critical drug metabolism and pharmacokinetics (DM/PK) parameters that should be taken into consideration in the process of drug discovery and development. The cell-free in [...] Read more.
Oral administration is the preferred and predominant route of choice for medication. As such, drug absorption is one of critical drug metabolism and pharmacokinetics (DM/PK) parameters that should be taken into consideration in the process of drug discovery and development. The cell-free in vitro parallel artificial membrane permeability assay (PAMPA) has been adopted as the primary screening to assess the passive diffusion of compounds in the practical applications. A classical quantitative structure–activity relationship (QSAR) model and a machine learning (ML)-based QSAR model were derived using the partial least square (PLS) scheme and hierarchical support vector regression (HSVR) scheme to elucidate the underlying passive diffusion mechanism and to predict the PAMPA effective permeability, respectively, in this study. It was observed that HSVR executed better than PLS as manifested by the predictions of the samples in the training set, test set, and outlier set as well as various statistical assessments. When applied to the mock test, which was designated to mimic real challenges, HSVR also showed better predictive performance. PLS, conversely, cannot cover some mechanistically interpretable relationships between descriptors and permeability. Accordingly, the synergy of predictive HSVR and interpretable PLS models can be greatly useful in facilitating drug discovery and development by predicting passive diffusion. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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21 pages, 5528 KiB  
Article
Quantitative Structure–Activity Relationships for Structurally Diverse Chemotypes Having Anti-Trypanosoma cruzi Activity
by Anacleto S. de Souza, Leonardo L. G. Ferreira, Aldo S. de Oliveira and Adriano D. Andricopulo
Int. J. Mol. Sci. 2019, 20(11), 2801; https://doi.org/10.3390/ijms20112801 - 8 Jun 2019
Cited by 20 | Viewed by 4759
Abstract
Small-molecule compounds that have promising activity against macromolecular targets from Trypanosoma cruzi occasionally fail when tested in whole-cell phenotypic assays. This outcome can be attributed to many factors, including inadequate physicochemical and pharmacokinetic properties. Unsuitable physicochemical profiles usually result in molecules with a [...] Read more.
Small-molecule compounds that have promising activity against macromolecular targets from Trypanosoma cruzi occasionally fail when tested in whole-cell phenotypic assays. This outcome can be attributed to many factors, including inadequate physicochemical and pharmacokinetic properties. Unsuitable physicochemical profiles usually result in molecules with a poor ability to cross cell membranes. Quantitative structure-activity relationship (QSAR) analysis is a valuable approach to the investigation of how physicochemical characteristics affect biological activity. In this study, artificial neural networks (ANNs) and kernel-based partial least squares regression (KPLS) were developed using anti-T. cruzi activity data for broadly diverse chemotypes. The models exhibited a good predictive ability for the test set compounds, yielding q2 values of 0.81 and 0.84 for the ANN and KPLS models, respectively. The results of this investigation highlighted privileged molecular scaffolds and the optimum physicochemical space associated with high anti-T. cruzi activity, which provided important guidelines for the design of novel trypanocidal agents having drug-like properties. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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20 pages, 12598 KiB  
Article
Three-Dimensional Quantitative Structure-Activity Relationships (3D-QSAR) on a Series of Piperazine-Carboxamides Fatty Acid Amide Hydrolase (FAAH) Inhibitors as a Useful Tool for the Design of New Cannabinoid Ligands
by Marcos Lorca, Yudisladys Valdes, Hery Chung, Javier Romero-Parra, C. David Pessoa-Mahana and Jaime Mella
Int. J. Mol. Sci. 2019, 20(10), 2510; https://doi.org/10.3390/ijms20102510 - 21 May 2019
Cited by 12 | Viewed by 3842
Abstract
Fatty Acid Amide Hydrolase (FAAH) is one of the main enzymes responsible for endocannabinoid metabolism. Inhibition of FAAH increases endogenous levels of fatty acid ethanolamides such as anandamide (AEA) and thus consitutes an indirect strategy that can be used to modulate endocannabinoid tone. [...] Read more.
Fatty Acid Amide Hydrolase (FAAH) is one of the main enzymes responsible for endocannabinoid metabolism. Inhibition of FAAH increases endogenous levels of fatty acid ethanolamides such as anandamide (AEA) and thus consitutes an indirect strategy that can be used to modulate endocannabinoid tone. In the present work, we present a three-dimensional quantitative structure-activity relationships/comparative molecular similarity indices analysis (3D-QSAR/CoMSIA) study on a series of 90 reported irreversible inhibitors of FAAH sharing a piperazine-carboxamide scaffold. The model obtained was extensively validated (q2 = 0.734; r2 = 0.966; r2m = 0.723). Finally, based on the information derived from the contour maps we designed a series of 10 new compounds with high predicted FAAH inhibition (predicted pIC50 of the best-proposed compounds = 12.196; 12.416). Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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10 pages, 5116 KiB  
Article
Structure-Based Approach for the Prediction of Mu-opioid Binding Affinity of Unclassified Designer Fentanyl-Like Molecules
by Giuseppe Floresta, Antonio Rescifina and Vincenzo Abbate
Int. J. Mol. Sci. 2019, 20(9), 2311; https://doi.org/10.3390/ijms20092311 - 10 May 2019
Cited by 19 | Viewed by 6186
Abstract
Three quantitative structure-activity relationship (QSAR) models for predicting the affinity of mu-opioid receptor (OR) ligands have been developed. The resulted models, exploiting the accessibility of the QSAR modeling, generate a useful tool for the investigation and identification of unclassified fentanyl-like structures. The models [...] Read more.
Three quantitative structure-activity relationship (QSAR) models for predicting the affinity of mu-opioid receptor (OR) ligands have been developed. The resulted models, exploiting the accessibility of the QSAR modeling, generate a useful tool for the investigation and identification of unclassified fentanyl-like structures. The models have been built using a set of 115 molecules using Forge as a software, and the quality was confirmed by statistical analysis, resulting in being effective for their predictive and descriptive capabilities. The three different approaches were then combined to produce a consensus model and were exploited to explore the chemical landscape of 3000 fentanyl-like structures, generated by a theoretical scaffold-hopping approach. The findings of this study should facilitate the identification and classification of new OR ligands with fentanyl-like structures. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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17 pages, 2428 KiB  
Article
Characterisation of Gas-Chromatographic Poly(Siloxane) Stationary Phases by Theoretical Molecular Descriptors and Prediction of McReynolds Constants
by Angelo A. D’Archivio and Andrea Giannitto
Int. J. Mol. Sci. 2019, 20(9), 2120; https://doi.org/10.3390/ijms20092120 - 29 Apr 2019
Cited by 5 | Viewed by 3267
Abstract
Retention in gas–liquid chromatography is mainly governed by the extent of intermolecular interactions between the solute and the stationary phase. While molecular descriptors of computational origin are commonly used to encode the effect of the solute structure in quantitative structure–retention relationship (QSRR) approaches, [...] Read more.
Retention in gas–liquid chromatography is mainly governed by the extent of intermolecular interactions between the solute and the stationary phase. While molecular descriptors of computational origin are commonly used to encode the effect of the solute structure in quantitative structure–retention relationship (QSRR) approaches, characterisation of stationary phases is historically based on empirical scales, the McReynolds system of phase constants being one of the most popular. In this work, poly(siloxane) stationary phases, which occupy a dominant position in modern gas–liquid chromatography, were characterised by theoretical molecular descriptors. With this aim, the first five McReynolds constants of 29 columns were modelled by multilinear regression (MLR) coupled with genetic algorithm (GA) variable selection applied to the molecular descriptors provided by software Dragon. The generalisation ability of the established GA-MLR models, evaluated by both external prediction and repeated calibration/evaluation splitting, was better than that reported in analogous studies regarding nonpolymeric (molecular) stationary phases. Principal component analysis on the significant molecular descriptors allowed to classify the poly(siloxanes) according to their chemical composition and partitioning properties. Development of QSRR-based models combining molecular descriptors of both solutes and stationary phases, which will be applied to transfer retention data among different columns, is in progress. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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10 pages, 5455 KiB  
Article
Prediction of the Auto-Ignition Temperatures of Binary Miscible Liquid Mixtures from Molecular Structures
by Shijing Shen, Yong Pan, Xianke Ji, Yuqing Ni and Juncheng Jiang
Int. J. Mol. Sci. 2019, 20(9), 2084; https://doi.org/10.3390/ijms20092084 - 27 Apr 2019
Cited by 13 | Viewed by 3435
Abstract
A quantitative structure-property relationship (QSPR) study is performed to predict the auto-ignition temperatures (AITs) of binary liquid mixtures based on their molecular structures. The Simplex Representation of Molecular Structure (SiRMS) methodology was employed to describe the structure characteristics of a series of 132 [...] Read more.
A quantitative structure-property relationship (QSPR) study is performed to predict the auto-ignition temperatures (AITs) of binary liquid mixtures based on their molecular structures. The Simplex Representation of Molecular Structure (SiRMS) methodology was employed to describe the structure characteristics of a series of 132 binary miscible liquid mixtures. The most rigorous “compounds out” strategy was employed to divide the dataset into the training set and test set. The genetic algorithm (GA) combined with multiple linear regression (MLR) was used to select the best subset of SiRMS descriptors, which significantly contributes to the AITs of binary liquid mixtures. The result is a multilinear model with six parameters. Various strategies were employed to validate the developed model, and the results showed that the model has satisfactory robustness and predictivity. Furthermore, the applicability domain (AD) of the model was defined. The developed model could be considered as a new way to reliably predict the AITs of existing or new binary miscible liquid mixtures, belonging to its AD. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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17 pages, 3448 KiB  
Article
An In Silico Model for Predicting Drug-Induced Hepatotoxicity
by Shuaibing He, Tianyuan Ye, Ruiying Wang, Chenyang Zhang, Xuelian Zhang, Guibo Sun and Xiaobo Sun
Int. J. Mol. Sci. 2019, 20(8), 1897; https://doi.org/10.3390/ijms20081897 - 17 Apr 2019
Cited by 77 | Viewed by 6998
Abstract
As one of the leading causes of drug failure in clinical trials, drug-induced liver injury (DILI) seriously impeded the development of new drugs. Assessing the DILI risk of drug candidates in advance has been considered as an effective strategy to decrease the rate [...] Read more.
As one of the leading causes of drug failure in clinical trials, drug-induced liver injury (DILI) seriously impeded the development of new drugs. Assessing the DILI risk of drug candidates in advance has been considered as an effective strategy to decrease the rate of attrition in drug discovery. Recently, there have been continuous attempts in the prediction of DILI. However, it indeed remains a huge challenge to predict DILI successfully. There is an urgent need to develop a quantitative structure–activity relationship (QSAR) model for predicting DILI with satisfactory performance. In this work, we reported a high-quality QSAR model for predicting the DILI risk of xenobiotics by incorporating the use of eight effective classifiers and molecular descriptors provided by Marvin. In model development, a large-scale and diverse dataset consisting of 1254 compounds for DILI was built through a comprehensive literature retrieval. The optimal model was attained by an ensemble method, averaging the probabilities from eight classifiers, with accuracy (ACC) of 0.783, sensitivity (SE) of 0.818, specificity (SP) of 0.748, and area under the receiver operating characteristic curve (AUC) of 0.859. For further validation, three external test sets and a large negative dataset were utilized. Consequently, both the internal and external validation indicated that our model outperformed prior studies significantly. Data provided by the current study will also be a valuable source for modeling/data mining in the future. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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25 pages, 3787 KiB  
Article
Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study
by Andrzej Bak, Violetta Kozik, Dariusz Kozakiewicz, Kamila Gajcy, Daniel Jan Strub, Aleksandra Swietlicka, Sarka Stepankova, Ales Imramovsky, Jaroslaw Polanski, Adam Smolinski and Josef Jampilek
Int. J. Mol. Sci. 2019, 20(7), 1524; https://doi.org/10.3390/ijms20071524 - 27 Mar 2019
Cited by 18 | Viewed by 5576
Abstract
A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. [...] Read more.
A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure–activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host–target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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14 pages, 1015 KiB  
Article
Quantitative Structure-Activity Relationship Study of Antioxidant Tripeptides Based on Model Population Analysis
by Baichuan Deng, Hongrong Long, Tianyue Tang, Xiaojun Ni, Jialuo Chen, Guangming Yang, Fan Zhang, Ruihua Cao, Dongsheng Cao, Maomao Zeng and Lunzhao Yi
Int. J. Mol. Sci. 2019, 20(4), 995; https://doi.org/10.3390/ijms20040995 - 25 Feb 2019
Cited by 23 | Viewed by 4591
Abstract
Due to their beneficial effects on human health, antioxidant peptides have attracted much attention from researchers. However, the structure-activity relationships of antioxidant peptides have not been fully understood. In this paper, quantitative structure-activity relationships (QSAR) models were built on two datasets, i.e., the [...] Read more.
Due to their beneficial effects on human health, antioxidant peptides have attracted much attention from researchers. However, the structure-activity relationships of antioxidant peptides have not been fully understood. In this paper, quantitative structure-activity relationships (QSAR) models were built on two datasets, i.e., the ferric thiocyanate (FTC) dataset and ferric-reducing antioxidant power (FRAP) dataset, containing 214 and 172 unique antioxidant tripeptides, respectively. Sixteen amino acid descriptors were used and model population analysis (MPA) was then applied to improve the QSAR models for better prediction performance. The results showed that, by applying MPA, the cross-validated coefficient of determination (Q2) was increased from 0.6170 to 0.7471 for the FTC dataset and from 0.4878 to 0.6088 for the FRAP dataset, respectively. These findings indicate that the integration of different amino acid descriptors provide additional information for model building and MPA can efficiently extract the information for better prediction performance. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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14 pages, 1085 KiB  
Article
Ciprofloxacin and Clinafloxacin Antibodies for an Immunoassay of Quinolones: Quantitative Structure–Activity Analysis of Cross-Reactivities
by Andrey A. Buglak, Ilya A. Shanin, Sergei A. Eremin, Hong-Tao Lei, Xiangmei Li, Anatoly V. Zherdev and Boris B. Dzantiev
Int. J. Mol. Sci. 2019, 20(2), 265; https://doi.org/10.3390/ijms20020265 - 11 Jan 2019
Cited by 12 | Viewed by 4957
Abstract
A common problem in the immunodetection of structurally close compounds is understanding the regularities of immune recognition, and elucidating the basic structural elements that provide it. Correct identification of these elements would allow for select immunogens to obtain antibodies with either wide specificity [...] Read more.
A common problem in the immunodetection of structurally close compounds is understanding the regularities of immune recognition, and elucidating the basic structural elements that provide it. Correct identification of these elements would allow for select immunogens to obtain antibodies with either wide specificity to different representatives of a given chemical class (for class-specific immunoassays), or narrow specificity to a unique compound (mono-specific immunoassays). Fluoroquinolones (FQs; antibiotic contaminants of animal-derived foods) are of particular interest for such research. We studied the structural basis of immune recognition of FQs by antibodies against ciprofloxacin (CIP) and clinafloxacin (CLI) as the immunizing hapten. CIP and CLI possess the same cyclopropyl substituents at the N1 position, while their substituents at C7 and C8 are different. Anti-CIP antibodies were specific to 22 of 24 FQs, while anti-CLI antibodies were specific to 11 of 26 FQs. The molecular size was critical for the binding between the FQs and the anti-CIP antibody. The presence of the cyclopropyl ring at the N1 position was important for the recognition between fluoroquinolones and the anti-CLI antibody. The anti-CIP quantitative structure–activity relationship (QSAR) model was well-equipped to predict the test set (pred_R2 = 0.944). The statistical parameters of the anti-CLI model were also high (R2 = 0.885, q2 = 0.864). Thus, the obtained QSAR models yielded sufficient correlation coefficients, internal stability, and predictive ability. This work broadens our knowledge of the molecular mechanisms of FQs’ interaction with antibodies, and it will contribute to the further development of antibiotic immunoassays. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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