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Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0

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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 (20 March 2024) | Viewed by 12886

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Special Issue Editor

Dr. Renata Tisi

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Guest Editor

Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy
Interests: signal transduction; calcium; molecular modeling; molecular dynamics; docking; mathematical modeling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, technical and scientifical progress in computational science has provided valuable and affordable tools for scientific research in the field of molecular biology. From bioinformatics to molecular modeling, from the -omics approach to the development of mathematical models, computational biomodeling has provided relevant contributions to the clarification of fundamental biological mechanisms.

For this Special Issue, we would like to invite papers that address the following concepts:

Integrated approach between wet and in silico techniques to tackle a relevant biological issue;
Exploitation of computational models to direct wet research;
Computational approach applied to gain novel interpretation of previous experimental data.

Suggested methodologies include, but are not limited to, bioinformatics, homology modelling, analysis of gene expression to identify transcriptional regulation pathways, protein–protein and ligand–protein docking, molecular dynamics, mathematical modeling, and molecular or cell biology techniques (not mandatory).

Dr. Renata Tisi
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 submissions that pass pre-check are 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

signal transduction
transcriptional regulation
molecular modeling
molecular dynamics
molecular docking
system biology
mathematical modeling
meta-analysis

Published Papers (10 papers)

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15 pages, 4902 KiB

Open AccessArticle

In Silico Description of the Direct Inhibition Mechanism of Endothelial Lipase by ANGPTL3

by Linda Montavoci, Omar Ben Mariem, Simona Saporiti, Tommaso Laurenzi, Luca Palazzolo, Alice Federica Ossoli, Uliano Guerrini, Laura Calabresi and Ivano Eberini

Int. J. Mol. Sci. 2024, 25(6), 3555; https://doi.org/10.3390/ijms25063555 - 21 Mar 2024

Viewed by 570

Abstract

Angiopoietin-like protein 3 (ANGPTL3) is a plasmatic protein that plays a crucial role in lipoprotein metabolism by inhibiting the lipoprotein lipase (LPL) and the endothelial lipase (EL) responsible for the hydrolysis of phospholipids on high-density lipoprotein (HDL). Interest in developing new pharmacological therapies aimed at inhibiting ANGPTL3 has been growing due to the hypolipidemic and antiatherogenic profile observed in its absence. The goal of this study was the in silico characterization of the interaction between ANGPTL3 and EL. Because of the lack of any structural information on both the trimeric coiled-coil N-terminal domain of ANGPTL3 and the EL homodimer as well as data regarding their interactions, the first step was to obtain the three-dimensional model of these two proteins. The models were then refined via molecular dynamics (MD) simulations and used to investigate the interaction mechanism. The analysis of interactions in different docking poses and their refinement via MD allowed the identification of three specific glutamates of ANGPTL3 that recognize a positively charged patch on the surface of EL. These ANGPTL3 key residues, i.e., Glu154, Glu157, and Glu160, could form a putative molecular recognition site for EL. This study paves the way for future investigations aimed at confirming the recognition site and at designing novel inhibitors of ANGPTL3. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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27 pages, 12276 KiB

Open AccessArticle

Deciphering “Immaturity-Stemness” in Human Epidermal Stem Cells at the Levels of Protein-Coding and Non-Coding Genomes: A Prospective Computational Approach

by Tatiana Vinasco-Sandoval, Gilles Lemaître, Pascal Soularue, Michèle T. Martin and Nicolas O. Fortunel

Int. J. Mol. Sci. 2024, 25(6), 3353; https://doi.org/10.3390/ijms25063353 - 15 Mar 2024

Viewed by 511

Abstract

The epidermis hosts populations of epithelial stem cells endowed with well-documented renewal and regenerative functions. This tissue thus constitutes a model for exploring the molecular characteristics of stem cells, which remain to date partially characterized at the molecular level in human skin. Our group has investigated the regulatory functions of the KLF4/TGFB1 and the MAD4/MAX/MYC signaling pathways in the control of the immaturity-stemness versus differentiation fate of keratinocyte stem and precursor cells from human interfollicular epidermis. We described that down-modulation of either KLF4 or MXD4/MAD4 using RNA interference tools promoted an augmented stemness cellular status; an effect which was associated with significant transcriptional changes, as assessed by RNA-sequencing. Here, we have implemented a computational approach aimed at integrating the level of the coding genome, comprising the transcripts encoding conventional proteins, and the non-coding genome, with a focus on long non-coding RNAs (lncRNAs). In addition, datasets of micro-RNAs (miRNAs) with validated functions were interrogated in view of identifying miRNAs that could make the link between protein-coding and non-coding transcripts. Putative regulons comprising both coding and long non-coding transcripts were built, which are expected to contain original pro-stemness candidate effectors available for functional validation approaches. In summary, interpretation of our basic functional data together with in silico biomodeling gave rise to a prospective picture of the complex constellation of transcripts regulating the keratinocyte stemness status. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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19 pages, 4741 KiB

Open AccessArticle

6-Amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides: Synthesis, Biological Activity, Quantum Chemical Studies and In Silico Docking Studies

by Victor V. Dotsenko, Alexander V. Bespalov, Anna E. Sinotsko, Azamat Z. Temerdashev, Vladimir K. Vasilin, Ekaterina A. Varzieva, Vladimir D. Strelkov, Nicolai A. Aksenov and Inna V. Aksenova

Int. J. Mol. Sci. 2024, 25(2), 769; https://doi.org/10.3390/ijms25020769 - 07 Jan 2024

Cited by 1 | Viewed by 883

Abstract

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N′-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or via a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalondianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichloro- phenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was confirmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computational scheme. The results revealed that the rate-limiting step is a cyclization process leading to the closure of the 1,4-dihydropyridine ring, with an activation barrier of 28.8 kcal/mol. Some of the dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were calculated and molecular docking studies were performed to identify potential protein targets. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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29 pages, 12923 KiB

Open AccessArticle

1,3-Dichloroadamantyl-Containing Ureas as Potential Triple Inhibitors of Soluble Epoxide Hydrolase, p38 MAPK and c-Raf

by Boris P. Gladkikh, Dmitry V. Danilov, Vladimir S. D’yachenko and Gennady M. Butov

Int. J. Mol. Sci. 2024, 25(1), 338; https://doi.org/10.3390/ijms25010338 - 26 Dec 2023

Viewed by 714

Abstract

Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of bioactive lipid signaling molecules. sEH converts epoxyeicosatrienoic acids (EET) to virtually inactive dihydroxyeicosatrienoic acids (DHET). The first acids are “medicinal” molecules, the second increase the inflammatory infiltration of cells. Mitogen-activated protein kinases (p38 MAPKs) are key protein kinases involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an important role in the regulation of cellular processes, especially inflammation. The proto-oncogenic serine/threonine protein kinase Raf (c-Raf) is a major component of the mitogen-activated protein kinase (MAPK) pathway: ERK1/2 signaling. Normal cellular Raf genes can also mutate and become oncogenes, overloading the activity of MEK1/2 and ERK1/2. The development of multitarget inhibitors is a promising strategy for the treatment of socially dangerous diseases. We synthesized 1,3-disubstituted ureas and diureas containing a dichloroadamantyl moiety. The results of computational methods show that soluble epoxide hydrolase inhibitors can act on two more targets in different signaling pathways of mitogen-activated protein kinases p38 MAPK and c-Raf. The two chlorine atoms in the adamantyl moiety may provide additional Cl-π interactions in the active site of human sEH. Molecular dynamics studies have shown that the stability of ligand–protein complexes largely depends on the “spacer effect.” The compound containing a bridge between the chloroadamantyl fragment and the ureide group forms more stable ligand–protein complexes with sEH and p38 MAPK, which indicates a better conformational ability of the molecule in the active sites of these targets. In turn, a compound containing two chlorine atoms forms a more stable complex with c-Raf, probably due to the presence of additional halogen bonds of chlorine atoms with amino acid residues. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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15 pages, 17489 KiB

Open AccessArticle

Role of Conformational Dynamics of Sulfotransferases SULT1A1 and SULT1A3 in Substrate Specificity

by Daniel Toth, Balint Dudas, Maria A. Miteva and Erika Balog

Int. J. Mol. Sci. 2023, 24(23), 16900; https://doi.org/10.3390/ijms242316900 - 29 Nov 2023

Viewed by 695

Abstract

Sulfotransferases (SULTs) are phase II metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-Phosphoadenosine 5′-Phosphosulfate (PAPS) to a wide variety of endogenous compounds, drugs and natural products. Although SULT1A1 and SULT1A3 share 93% identity, SULT1A1, the most abundant SULT isoform in humans, exhibits a broad substrate range with specificity for small phenolic compounds, while SULT1A3 displays a high affinity toward monoamine neurotransmitters like dopamine. To elucidate the factors determining the substrate specificity of the SULT1 isoenzymes, we studied the dynamic behavior and structural specificities of SULT1A1 and SULT1A3 by using molecular dynamics (MD) simulations and ensemble docking of common and specific substrates of the two isoforms. Our results demonstrated that while SULT1A1 exhibits a relatively rigid structure by showing lower conformational flexibility except for the lip (loop L1), the loop L2 and the cap (L3) of SULT1A3 are extremely flexible. We identified protein residues strongly involved in the recognition of different substrates for the two isoforms. Our analyses indicated that being more specific and highly flexible, the structure of SULT1A3 has particularities in the binding site, which are crucial for its substrate selectivity. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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17 pages, 4865 KiB

Open AccessArticle

Enhancing Giardicidal Activity and Aqueous Solubility through the Development of “RetroABZ”, a Regioisomer of Albendazole: In Vitro, In Vivo, and In Silico Studies

by Carlos Martínez-Conde, Blanca Colín-Lozano, Abraham Gutiérrez-Hernández, Emanuel Hernández-Núñez, Lilián Yépez-Mulia, Luis Fernando Colorado-Pablo, Rodrigo Aguayo-Ortiz, Jaime Escalante, Julio C. Rivera-Leyva, Jessica Nayelli Sánchez-Carranza, Elizabeth Barbosa-Cabrera and Gabriel Navarrete-Vazquez

Int. J. Mol. Sci. 2023, 24(19), 14949; https://doi.org/10.3390/ijms241914949 - 06 Oct 2023

Viewed by 1389

Abstract

Parasitic diseases, including giardiasis caused by Giardia lamblia (G. lamblia), present a considerable global health burden. The limited effectiveness and adverse effects of current treatment options underscore the necessity for novel therapeutic compounds. In this study, we employed a rational design strategy to synthesize retroalbendazole (RetroABZ), aiming to address the limitations associated with albendazole, a commonly used drug for giardiasis treatment. RetroABZ exhibited enhanced in vitro activity against G. lamblia trophozoites, demonstrating nanomolar potency (IC₅₀ = 83 nM), outperforming albendazole (189 nM). Moreover, our in vivo murine model of giardiasis displayed a strong correlation, supporting the efficacy of RetroABZ, which exhibited an eleven-fold increase in potency compared to albendazole, with median effective dose (ED₅₀) values of 5 µg/kg and 55 µg/kg, respectively. A notable finding was RetroABZ’s significantly improved water solubility (245.74 µg/mL), representing a 23-fold increase compared to albendazole, thereby offering potential opportunities for developing derivatives that effectively target invasive parasites. The molecular docking study revealed that RetroABZ displays an interaction profile with tubulin similar to albendazole, forming hydrogen bonds with Glu198 and Cys236 of the β-tubulin. Additionally, molecular dynamics studies demonstrated that RetroABZ has a greater number of hydrophobic interactions with the binding site in the β-tubulin, due to the orientation of the propylthio substituent. Consequently, RetroABZ exhibited a higher affinity compared to albendazole. Overall, our findings underscore RetroABZ’s potential as a promising therapeutic candidate not only for giardiasis but also for other parasitic diseases. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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16 pages, 1691 KiB

Open AccessArticle

In Silico Neuroprotective Effects of Specific Rheum palmatum Metabolites on Parkinson’s Disease Targets

by Patrick Jay B. Garcia, Steven Kuan-Hua Huang, Kathlia A. De Castro-Cruz, Rhoda B. Leron and Po-Wei Tsai

Int. J. Mol. Sci. 2023, 24(18), 13929; https://doi.org/10.3390/ijms241813929 - 11 Sep 2023

Viewed by 1670

Abstract

Parkinson’s disease (PD) is one of the large-scale health issues detrimental to human quality of life, and current treatments are only focused on neuroprotection and easing symptoms. This study evaluated in silico binding activity and estimated the stability of major metabolites in the roots of R. palmatum (RP) with main protein targets in Parkinson’s disease and their ADMET properties. The major metabolites of RP were subjected to molecular docking and QSAR with α-synuclein, monoamine oxidase isoform B, catechol o-methyltransferase, and A_2A adenosine receptor. From this, emodin had the greatest binding activity with Parkinson’s disease targets. The chemical stability of the selected compounds was estimated using density functional theory analyses. The docked compounds showed good stability for inhibitory action compared to dopamine and levodopa. According to their structure–activity relationship, aloe-emodin, chrysophanol, emodin, and rhein exhibited good inhibitory activity to specific targets. Finally, mediocre pharmacokinetic properties were observed due to unexceptional blood–brain barrier penetration and safety profile. It was revealed that the major metabolites of RP may have good neuroprotective activity as an additional hit for PD drug development. Also, an association between redox-mediating and activities with PD-relevant protein targets was observed, potentially opening discussion on electrochemical mechanisms with biological functions. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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22 pages, 7543 KiB

Open AccessArticle

Assessments of Alpha-Amylase Inhibitory Potential of Tagetes Flavonoids through In Vitro, Molecular Docking, and Molecular Dynamics Simulation Studies

by Gamal A. Mohamed, Abdelsattar M. Omar, Moustafa E. El-Araby, Shaza Mass and Sabrin R. M. Ibrahim

Int. J. Mol. Sci. 2023, 24(12), 10195; https://doi.org/10.3390/ijms241210195 - 15 Jun 2023

Cited by 4 | Viewed by 1608

Abstract

Diabetes is a chronic fast-growing metabolic disorder that is characterized by high blood glucose levels. Tagetes minuta L. has been used as a traditional remedy for various illnesses for many years, and, furthermore, its oil is used in the perfume and flavor industries. T. minuta contains various metabolites, such as flavonoids, thiophenes, terpenes, sterols, and phenolics, with varied bioactivities. Flavonoids can inhibit carbohydrate-digesting enzymes, such as alpha-amylase, which is a convenient dietary strategy for controlling hyperglycemia. In the current investigation, the isolated flavonoids quercetagetin-6-O-(6-O-caffeoyl-β-D-glucopyranoside), quercetagetin-7-O-β-D-glucopyranoside, quercetagetin-6-O-β-D-glucopyranoside, minutaside A, patuletin-7-O-β-D-glucopyranoside, quercetagetin-7-methoxy-6-O-β-D-glucopyranoside, tagenols A and B, quercetagetin-3,7-dimethoxy-6-O-β-D-glucopyranoside, patuletin, quercetin-3,6-dimethyl ether, and quercetin-3-methyl ether from T. minuta were assessed for their alpha-amylase inhibition (AAI) efficacy using an in vitro assay, as well as molecular docking, dynamics simulation, and ADMET analyses. Our findings show that quercetagetin-6-O-(6-O-caffeoyl-β-D-glucopyranoside) (1), quercetagetin-7-O-β-D-glucopyranoside (2), quercetagetin-6-O-β-D-glucopyranoside (3), minutaside A (4), patuletin-7-O-β-D-glucopyranoside (5), and quercetagetin-7-methoxy-6-O-β-D-glucopyranoside (6) had a notable AAI capacity (IC₅₀s ranged from 7.8 to 10.1 μM) compared to acarbose (IC₅₀ 7.1 μM). Furthermore, these compounds with the highest binding affinity among the tested flavonoids revealed high docking scores for AA (ranging from −12.171 to 13.882 kcal/mol) compared to that of acarbose (−14.668 kcal/mol). In MDS, these compounds were observed to show maximum stability and the greatest binding free energy, suggesting that they may contend with native ligands. In addition, the ADMET analysis showed that these active compounds had a broad span of drug-like, pharmacokinetic, and physicochemical features and did not possess any considerable undesired effects. The current results suggest the potential of these metabolites as AAI candidates. However, further in vivo and mechanistic studies are warranted to specify the efficacy of these metabolites. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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16 pages, 2195 KiB

Open AccessArticle

Using Machine Learning and Molecular Docking to Leverage Urease Inhibition Data for Virtual Screening

by Natália Aniceto, Tânia S. Albuquerque, Vasco D. B. Bonifácio, Rita C. Guedes and Nuno Martinho

Int. J. Mol. Sci. 2023, 24(9), 8180; https://doi.org/10.3390/ijms24098180 - 03 May 2023

Cited by 1 | Viewed by 2201

Abstract

Urease is a metalloenzyme that catalyzes the hydrolysis of urea, and its modulation has an important role in both the agricultural and medical industry. Even though numerous molecules have been tested against ureases of different species, their clinical translation has been limited due to chemical and metabolic stability as well as side effects. Therefore, screening new compounds against urease would be of interest in part due to rising concerns regarding antibiotic resistance. In this work, we collected and curated a diverse set of 2640 publicly available small-molecule inhibitors of jack bean urease and developed a classifier using a random forest machine learning method with high predictive performance. In addition, the physicochemical features of compounds were paired with molecular docking and protein–ligand fingerprint analysis to gather insight into the current activity landscape. We observed that the docking score could not differentiate active from inactive compounds within each chemical family, but scores were correlated with compound activity when all compounds were considered. Additionally, a decision tree model was built based on 2D and 3D Morgan fingerprints to mine patterns of the known active-class compounds. The final machine learning model showed good prediction performance against the test set (81% and 77% precision for active and inactive compounds, respectively). Finally, this model was employed, as a proof-of-concept, on an in-house library to predict new hits that were then tested against urease and found to be active. This is, to date, the largest, most diverse dataset of compounds used to develop predictive in silico models. Overall, the results highlight the usefulness of using machine learning classifiers and molecular docking to predict novel urease inhibitors. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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Review

Jump to: Research

16 pages, 4068 KiB

Open AccessReview

Dynamic Properties of the DNA Damage Response Mre11/Rad50 Complex

by Jacopo Vertemara and Renata Tisi

Int. J. Mol. Sci. 2023, 24(15), 12377; https://doi.org/10.3390/ijms241512377 - 03 Aug 2023

Cited by 2 | Viewed by 1312

Abstract

DNA double-strand breaks (DSBs) are a significant threat to cell viability due to the induction of genome instability and the potential loss of genetic information. One of the key players for early DNA damage response is the conserved Mre11/Rad50 Nbs1/Xrs2 (MRN/X) complex, which is quickly recruited to the DNA’s ruptured ends and is required for their tethering and their subsequent repair via different pathways. The MRN/X complex associates with several other proteins to exert its functions, but it also exploits sophisticated internal dynamic properties to orchestrate the several steps required to address the damage. In this review, we summarize the intrinsic molecular features of the MRN/X complex through biophysical, structural, and computational analyses in order to describe the conformational transitions that allow for this complex to accomplish its multiple functions. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms 2.0)

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