E-Mail Alert

Add your e-mail address to receive forthcoming issues of this journal:

Journal Browser

Journal Browser

Special Issue "Frontiers in Computational Chemistry for Drug Discovery"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 September 2017)

Special Issue Editor

Guest Editor
Prof. Dr. F. Javier Luque

Department of Nutrition, Food Science, and Gastronomy and Institute of Biomedicine, University of Barcelona, Av. Prat de la Riba 171, 08921 Santa Coloma de Gramenet, Spain
Website | E-Mail
Interests: computational biology; molecular interactions; ligand-receptor binding; structure-based drug design

Special Issue Information

Dear Colleagues,

Nowadays, computational methods pervade almost all aspects of drug discovery. Computer-assisted tools contribute to the decision-making process along the entire drug discovery pipeline, including the validation of suitable targets, high-throughput screening of molecular libraries, optimization of lead compounds, and the balance between pharmacological potency and physico-chemical and pharmacokinetic properties. This tendency will be reinforced in the next few years due to the continued increases in computer power, and the elaboration of sophisticated algorithms to capture the physico-chemical principles that underlie the activity of drugs. This effort should enable drug discovery methodology to evolve from approximate to more rigorous methods. How should computational methods evolve to ameliorate the success of drug discovery? The answer to this question is related to the identification of the current limitations faced by computational algorithms to unveil the delicate balance between factors that determine both potency and ADMET properties of drug candidates. This Special Issue aims to provide a forum for the dissemination of the latest information on new computational approaches and methods in the exciting area of drug discovery.

We welcome original articles and short communications, as well as a limited number of review articles, on new approaches and methods of computational chemistry for drug discovery. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on the website.

Prof. Dr. F. Javier Luque
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug discovery
  • ligand-receptor recognition
  • binding affinity
  • binding kinetics
  • computational chemistry
  • enhanced sampling techniques
  • quantum mechanics
  • solvation
  • free energy methods
  • structure-based design

Published Papers (5 papers)

View options order results:
result details:
Displaying articles 1-5
Export citation of selected articles as:

Research

Open AccessFeature PaperArticle Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors
Molecules 2017, 22(11), 1945; doi:10.3390/molecules22111945
Received: 20 October 2017 / Revised: 7 November 2017 / Accepted: 8 November 2017 / Published: 10 November 2017
PDF Full-text (4569 KB) | HTML Full-text | XML Full-text
Abstract
The four receptors that signal for adenosine, A1, A2A, A2B and A3 ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical
[...] Read more.
The four receptors that signal for adenosine, A1, A2A, A2B and A3 ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A2A, and lately the A1 ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first in silico mutagenesis on the A1AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A2AAR, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A2BAR, and the use of FEP as a tool for bioisosteric design on the A3AR. Full article
(This article belongs to the Special Issue Frontiers in Computational Chemistry for Drug Discovery)
Figures

Figure 1

Open AccessArticle Rapid Screening of Active Components with an Osteoclastic Inhibitory Effect in Herba epimedii Using Quantitative Pattern–Activity Relationships Based on Joint-Action Models
Molecules 2017, 22(10), 1767; doi:10.3390/molecules22101767
Received: 7 October 2017 / Revised: 14 October 2017 / Accepted: 16 October 2017 / Published: 19 October 2017
PDF Full-text (2630 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Screening of bioactive components is important for modernization and quality control of herbal medicines, while the traditional bioassay-guided phytochemical approach is time-consuming and laborious. The presented study proposes a strategy for rapid screening of active components from herbal medicines. As a case study,
[...] Read more.
Screening of bioactive components is important for modernization and quality control of herbal medicines, while the traditional bioassay-guided phytochemical approach is time-consuming and laborious. The presented study proposes a strategy for rapid screening of active components from herbal medicines. As a case study, the quantitative pattern–activity relationship (QPAR) between compounds and the osteoclastic inhibitory effect of Herba epimedii, a widely used herbal medicine in China, were investigated based on joint models. For model construction, standard mixtures data showed that the joint-action models are better than the partial least-squares (PLS) model. Then, the Good2bad value, which could reflect components’ importance based on Monte Carlo sampling, was coupled with the joint-action models for screening of active components. A compound (baohuoside I) and a component composed of compounds with retention times in the 6.9–7.9 min range were selected by our method. Their inhibition rates were higher than icariin, the key bioactive compound in Herba epimedii, which could inhibit osteoclast differentiation and bone resorption in a previous study. Meanwhile, the half-maximal effective concentration, namely, EC50 value of the selected component was 7.54 μg/mL, much smaller than that of baohuoside I—77 μg/mL—which indicated that there is synergistic action between compounds in the selected component. The results clearly show our proposed method is simple and effective in screening the most-bioactive components and compounds, as well as drug-lead components, from herbal medicines. Full article
(This article belongs to the Special Issue Frontiers in Computational Chemistry for Drug Discovery)
Figures

Open AccessArticle Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA
Molecules 2017, 22(8), 1358; doi:10.3390/molecules22081358
Received: 2 August 2017 / Revised: 13 August 2017 / Accepted: 13 August 2017 / Published: 16 August 2017
Cited by 1 | PDF Full-text (2800 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The transcription factor p53 is a potent tumor suppressor dubbed as the “guardian of the genome” because of its ability to orchestrate protective biological outputs in response to a variety of oncogenic stresses. Mutation and thus inactivation of p53 can be found in
[...] Read more.
The transcription factor p53 is a potent tumor suppressor dubbed as the “guardian of the genome” because of its ability to orchestrate protective biological outputs in response to a variety of oncogenic stresses. Mutation and thus inactivation of p53 can be found in 50% of human tumors. The majority are missense mutations located in the DNA binding region. Among them, G245S is known to be a structural hotspot mutation. To understand the behaviors and differences between the wild-type and mutant, both a dimer of the wild type p53 (wt-p53) and its G245S mutant (G245S-mp53), complexed with DNA, were simulated using molecular dynamics for more than 1 μs. wt-p53 and G245S-mp53 apo monomers were simulated for 1 μs as well. Conformational analyses and binding energy evaluations performed underline important differences and therefore provide insights to understand the G245S-mp53 loss of function. Our results indicate that the G245S mutation destabilizes several structural regions in the protein that are crucial for DNA binding when found in its apo form and highlight differences in the mutant-DNA complex structure compared to the wt protein. These findings not only provide means that can be applied to other p53 mutants but also serve as structural basis for further studies aimed at the development of cancer therapies based on restoring the function of p53. Full article
(This article belongs to the Special Issue Frontiers in Computational Chemistry for Drug Discovery)
Figures

Figure 1

Open AccessArticle Metal Atom Effect on the Photophysical Properties of Mg(II), Zn(II), Cd(II), and Pd(II) Tetraphenylporphyrin Complexes Proposed as Possible Drugs in Photodynamic Therapy
Molecules 2017, 22(7), 1093; doi:10.3390/molecules22071093
Received: 26 May 2017 / Revised: 22 June 2017 / Accepted: 28 June 2017 / Published: 30 June 2017
Cited by 1 | PDF Full-text (1557 KB) | HTML Full-text | XML Full-text
Abstract
The effects of Mg, Zn, Cd, and Pd dications on the photophysical properties of the tetraphenylporphyrin ligand have been explored, considering the corresponding complexes and by using the density functional theory and its time-dependent extension. Results show that absorption wavelengths do not change
[...] Read more.
The effects of Mg, Zn, Cd, and Pd dications on the photophysical properties of the tetraphenylporphyrin ligand have been explored, considering the corresponding complexes and by using the density functional theory and its time-dependent extension. Results show that absorption wavelengths do not change significantly when the metal ion changes contrary to what happens to the singlet–triplet energy gaps (ΔES−T) and the spin-orbit matrix elements ΨSnHsoΨTm. The most probable intersystem spin crossing (ISC) pathways for the population of the lowest triplet states have been explored. Our findings can contribute to rationalize the available experimental data and promote the potential therapeutic use of these compounds as photosensitizers in photodynamic therapy (PDT). Full article
(This article belongs to the Special Issue Frontiers in Computational Chemistry for Drug Discovery)
Figures

Open AccessArticle Exploring the Pivotal Role of the CK2 Hinge Region Sub-Pocket in Binding with Tricyclic Quinolone Analogues by Computational Analysis
Molecules 2017, 22(5), 840; doi:10.3390/molecules22050840
Received: 14 April 2017 / Revised: 12 May 2017 / Accepted: 17 May 2017 / Published: 19 May 2017
PDF Full-text (2453 KB) | HTML Full-text | XML Full-text
Abstract
Protein kinase CK2 has been considered as an attractive therapeutic target of cancer therapy. The tricyclic quinoline compound CX-4945 is the first representative of CK2 inhibitors used in human clinical trials. The binding of non-2,6-naphtyridine substituted compounds 27e (IC50 > 500 nM)
[...] Read more.
Protein kinase CK2 has been considered as an attractive therapeutic target of cancer therapy. The tricyclic quinoline compound CX-4945 is the first representative of CK2 inhibitors used in human clinical trials. The binding of non-2,6-naphtyridine substituted compounds 27e (IC50 > 500 nM) and 27h (IC50 > 1000 nM) to CK2 is abolished. However, the unbinding mechanisms due to the key pharmacophore group replacement of compounds 27e and 27h are unveiled. In the present work, combined computational analysis was performed to investigate the underlying structural basis of the low-affinity of two systems. As indicated in the results, the loss of hydrogen bonds between the non-2,6-naphtyridine and the hinge region destroyed the proper recognition of the two complexes. Besides, the allosteric mechanisms between the deviated ligands and the changed regions (G-loop, C-loop and β4/β5 loop) are proposed. Furthermore, energetic analysis was evaluated by detailed energy calculation and residue-based energy decomposition. More importantly, the summary of known polar pharmacophore groups elucidates the pivotal roles of hinge region sub-pocket in the binding of CK2 inhibitors. These results provide rational clues to the fragment-based design of more potent CK2 inhibitors. Full article
(This article belongs to the Special Issue Frontiers in Computational Chemistry for Drug Discovery)
Figures

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Metal atom effect on the photophysical properties of Mg (II), Zn(II), Cd(II) and Pd(II) tetraphenylporphyrin complexes proposed as possible drugs in photodynamic therapy
Author: Nino Russo
Affiliation: Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, I-87036 Arcavacata di Rende, Italy
Abstract: The effects of the Mg, Zn, Cd and Pd ions in the photophysical properties of the tetraphenylporphyrin ligand have been explored considering the relative complexes and by using the density functional theory and its time-depend extension. Result show as the absorption wavelengths do not change significantly but the singlet-triplet energy gaps (DES-T) and the spin-orbit matrix elements (|ĤSO|) results to be effected. The most probable intersystem spin crossing (ISC) pathways for the activation of the lowest triplet states, have been explored. On the basis of our results we can rationalize the available experimental data and predict the potential therapeutic use of these compounds as photosensitizers in photodynamic therapy (PDT).

Title: The Semiempirical Quantum Mechanical Scoring Functions for Protein-Ligand Interactions
Authors: Adam Pecina 1, Jindřich Fanfrlík 1, Jan Řezáč 1, Martin Lepšík 1 and Pavel Hobza 1,2*
Affiliation: 1 Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 Prague 6, Czech Republic
2 Regional Centre of Advanced Technologies and Materials, Palacký University, 77146 Olomouc, Czech Republic
Abstract: General and reliable description of structures and energetics in protein-ligand binding using the docking/scoring methodology has up to now been elusive. We address this urgent deficiency of scoring function by systematic development of corrected semiempirical quantum mechanical (SQM) methods which correctly describe all types of non-covalent interactions and are fast enough to treat systems of thousands of atoms. Two most accurate SQM methods, PM6-D3H4X and SCC-DF-TB3-D3H4X, are coupled with the COSMO implicit solvation model in so called “SQM/COSMO” scoring functions and have shown unique recognition of native ligand pose in cognate docking and ligand ranking in challenging protein-ligand systems, including metalloproteins. This method, due to its generality, comparability across the chemical space and no need for any system-specific parameters, gives promise to become in the near future a useful computational tool in structure-based drug design or serve as a reference method to judge the performance of other scoring functions.

Title: Using molecular dynamics to understand allosteric regulation by phosphorylation: the HDAC8 case
Authors: M. Pujadas, M. Bhattacharyya, M. Martínez, X. Barril
Abstract: Histone deacetylases (HDACs) remove the acetyl groups from ε-N-acetyl lysine on histone tails. As this activity modulates transcriptional activity and cell cycle, HDACs are an important class of pharmacological targets. Uniquely amongst this protein class, HDAC8 is regulated by posttranslational phosphorylation at the non-catalytic, non-conserved N-terminal residue Ser39. Structural information suggests that the negative residues surrounding Ser39 experience major electrostatic repulsion and structural disruption upon phosphorylation. Here we use molecular dynamics simulations to investigate the structural and dynamic consequences of phosphorylation, finding that allosteric regulation involves much subtler and longer range effects. Site directed mutagenesis experiments support the predicted allosteric circuit.

Title: Dynamic docking: a paradigm shift in computational drug discovery
Authors: Dario GIoia, Martina Bertazzo, Maurizio Recanatini, Federico Falchi, Matteo Masetti and Andrea Cavalli
Abstract: Molecular docking is the methodology of choice for studying in silico protein-ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations mostly related to the treatment of ligands and targets statically or semi-flexibly. They also neglect solvation and entropic effects, which strongly limit their predictive power. During the last decade, full atomistic molecular dynamics (MD)-based methods have emerged as a valid alternative to simulate macromolecular complexes. Compared to traditional docking, MD in principle allows the full exploration of drug-target recognition and binding from both the mechanistic and energetic point of view (dynamic docking). In addition, binding and unbinding kinetic constants can also be determined. While dynamic docking is still too computationally expensive to be routinely employed in fast paced drug discovery programs, the advent of faster computing architectures and advanced simulation methodologies are changing this scenario. It is foreseeable that dynamic docking will replace static docking approaches in the near future, leading to a major paradigm shift in the way in silico drug discovery is conceived. Based on these premises, here we review the main milestones that have paved the way for such advancement in the field

Title: Accurate estimation of the standard binding free energy of netropsin with DNA.
List of Authors: Christophe Chipot, Hugo Gattuso, Elise Dumont, Antonio Monari, François Dehez.
Abstract: DNA is the target of a host of chemical compounds (drugs, pollutants, photosensitizers, ...) through non-covalent interactions. Depending on their structure and chemical properties, DNA binders can associate to the minor or the major groove of double-stranded DNA, they can also intercalate between two adjacent base pairs, or even replace one or two base pairs within the DNA double helix. The subsequent biological effects are tightly associated to the architecture of the binding motif. Discriminating between the different binding patterns is of paramount importance to predict and rationalize the effect of a given compound on DNA. The structural characterization of DNA complexes remains however cumbersome at the experimental level. In this contribution, we employed all-atoms molecular-dynamics simulations to determine the standard binding free energy of DNA with netropsin, a well-characterized antiviral and antimicrobial drug, which associates to the minor groove of double stranded DNA. To overcome the sampling limitations of classical molecular dynamics simulations, which cannot capture the large change in configurational entropy that accompanies binding, we resort to a series of potentials of mean force (PMF) calculations involving a set of geometrical restraints acting on collective variables.

Title: Structure-based design of potent adenosine receptors
List of Authors: Willem Jespers, Ana Oliveira, Rubén Prieto-Díaz, María Majellaro, Eddy Sotelo, Johan Åqvist and Hugo Gutierrez-de-Teran
Abstract: The four receptors that signal for adenosine, A1, A2A, A2B and A3 ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A2A, and lately the A1 ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first “in silico” mutagenesis on the A1 receptor here reported allows understanding the specificity and high affinity of the DPCPX xanthine-antagonist. On the A2A receptor, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A2BAR, and the use of FEP as a tool for bioisosteric design on the A3AR.

Back to Top