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Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications 2020

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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 (31 March 2021) | Viewed by 14900

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Special Issue Editor

Prof. Dr. Alexandre G. De Brevern

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Guest Editor

Department of Biological Research on the Red Blood Cells, INTS, INSERM UMR_S 1134, Université de Paris, Université de la Réunion, 75739 Paris, France
Interests: structural bioinformatics; bioinformatics; next-generation sequence; drug design; deep learning
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Protein–ligand interactions play a fundamental role in most major biological functions, but also in drug discovery. With the increasing structural information of proteins and protein–ligand complexes, molecular modelling, molecular dynamics, and chemoinformatics approaches are often required for the efficient analysis of a large number of such complexes and to provide insights. Similarly, numerous computational approaches have been developed to characterize and use the knowledge of such interactions, which can lead to drug candidates. For instance, one main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. This new information brings questions that affect chemistry, biology, and even poses specific computer problems. Papers related to any aspect of protein–ligand analysis and/or prediction using computational approaches, as well as new developments dedicated to these tasks, will be considered for this Special Issue.

Prof. Dr. Alexandre G. de Brevern
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

Protein–ligand analysis
Protein–ligand interaction fingerprints
Structure protein–ligand interaction relationships
Structure–activity relationships
Molecular modeling
Molecular dynamics
Chemogenomics
Chemical biology
Drug discovery and design
Fragment-based lead discovery
2D interaction maps
3D activity
Hot spots
Pharmacophore

Published Papers (5 papers)

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Research

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26 pages, 3675 KiB

Open AccessArticle

‘All That Glitters Is Not Gold’: High-Resolution Crystal Structures of Ligand-Protein Complexes Need Not Always Represent Confident Binding Poses

by Sohini Chakraborti, Kaushik Hatti and Narayanaswamy Srinivasan

Int. J. Mol. Sci. 2021, 22(13), 6830; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136830 - 25 Jun 2021

Cited by 5 | Viewed by 2728

Abstract

Our understanding of the structure–function relationships of biomolecules and thereby applying it to drug discovery programs are substantially dependent on the availability of the structural information of ligand–protein complexes. However, the correct interpretation of the electron density of a small molecule bound to a crystal structure of a macromolecule is not trivial. Our analysis involving quality assessment of ~0.28 million small molecule–protein binding site pairs derived from crystal structures corresponding to ~66,000 PDB entries indicates that the majority (65%) of the pairs might need little (54%) or no (11%) attention. Out of the remaining 35% of pairs that need attention, 11% of the pairs (including structures with high/moderate resolution) pose serious concerns. Unfortunately, most users of crystal structures lack the training to evaluate the quality of a crystal structure against its experimental data and, in general, rely on the resolution as a ‘gold standard’ quality metric. Our work aims to sensitize the non-crystallographers that resolution, which is a global quality metric, need not be an accurate indicator of local structural quality. In this article, we demonstrate the use of several freely available tools that quantify local structural quality and are easy to use from a non-crystallographer’s perspective. We further propose a few solutions for consideration by the scientific community to promote quality research in structural biology and applied areas. Full article

(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications 2020)

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16 pages, 3409 KiB

Open AccessArticle

Comparative Study of Interactions between Human cGAS and Inhibitors: Insights from Molecular Dynamics and MM/PBSA Studies

by Xiaowen Wang and Wenjin Li

Int. J. Mol. Sci. 2021, 22(3), 1164; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031164 - 25 Jan 2021

Cited by 3 | Viewed by 2063

Abstract

Recent studies have identified cyclic GMP-AMP synthase (cGAS) as an important target for treating autoimmune diseases, and several inhibitors of human cGAS (hcGAS) and their structures in complexation with hcGAS have been reported. However, the mechanisms via which these inhibitors interact with hcGAS are not completely understood. Here, we aimed to assess the performance of molecular mechanics/Poisson–Boltzmann solvent-accessible surface area (MM/PBSA) in evaluating the binding affinity of various hcGAS inhibitors and to elucidate their detailed interactions with hcGAS from an energetic viewpoint. Using molecular dynamics (MD) simulation and MM/PBSA approaches, the estimated free energies were in good agreement with the experimental ones, with a Pearson’s correlation coefficient and Spearman’s rank coefficient of 0.67 and 0.46, respectively. In per-residue energy decomposition analysis, four residues, K362, R376, Y436, and K439 in hcGAS were found to contribute significantly to the binding with inhibitors via hydrogen bonding, salt bridges, and various π interactions, such as π· · ·π stacking, cation· · ·π, hydroxyl· · ·π, and alkyl· · ·π interactions. In addition, we discussed other key interactions between specific residues and ligands, in particular, between H363 and JUJ, F379 and 9BY, and H437 and 8ZM. The sandwiched structures of the inhibitor bound to the guanidinium group of R376 and the phenyl ring of Y436 were also consistent with the experimental data. The results indicated that MM/PBSA in combination with other virtual screening methods, could be a reliable approach to discover new hcGAS inhibitors and thus is valuable for potential treatments of cGAS-dependent inflammatory diseases. Full article

(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications 2020)

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15 pages, 3049 KiB

Open AccessArticle

Babesia Bovis Ligand-Receptor Interaction: AMA-1 Contains Small Regions Governing Bovine Erythrocyte Binding

by Laura Cuy-Chaparro, Michel David Bohórquez, Gabriela Arévalo-Pinzón, Jeimmy Johana Castañeda-Ramírez, Carlos Fernando Suárez, Laura Pabón, Diego Ordóñez, Gina Marcela Gallego-López, Carlos Esteban Suárez, Darwin Andrés Moreno-Pérez and Manuel Alfonso Patarroyo

Int. J. Mol. Sci. 2021, 22(2), 714; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020714 - 13 Jan 2021

Cited by 5 | Viewed by 2842

Abstract

Apical membrane antigen 1 is a microneme protein which plays an indispensable role during Apicomplexa parasite invasion. The detailed mechanism of AMA-1 molecular interaction with its receptor on bovine erythrocytes has not been completely defined in Babesia bovis. This study was focused on identifying the minimum B. bovis AMA-1-derived regions governing specific and high-affinity binding to its target cells. Different approaches were used for detecting ama-1 locus genetic variability and natural selection signatures. The binding properties of twelve highly conserved 20-residue-long peptides were evaluated using a sensitive and specific binding assay based on radio-iodination. B. bovis AMA-1 ectodomain structure was modelled and refined using molecular modelling software. NetMHCIIpan software was used for calculating B- and T-cell epitopes. The B. bovis ama-1 gene had regions under functional constraint, having the highest negative selective pressure intensity in the Domain I encoding region. Interestingly, B. bovis AMA-1-DI (¹⁰⁰YMQKFDIPRNHGSGIYVDLG¹¹⁹ and ¹²⁰GYESVGSKSYRMPVGKCPVV¹³⁹) and DII (³⁰²CPMHPVRDAIFGKWSGGSCV³²¹)-derived peptides had high specificity interaction with erythrocytes and bound to a chymotrypsin and neuraminidase-treatment sensitive receptor. DI-derived peptides appear to be exposed on the protein’s surface and contain predicted B- and T-cell epitopes. These findings provide data (for the first-time) concerning B. bovis AMA-1 functional subunits which are important for establishing receptor-ligand interactions which could be used in synthetic vaccine development. Full article

(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications 2020)

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14 pages, 2559 KiB

Open AccessArticle

Predicting Drug-Target Interactions with Electrotopological State Fingerprints and Amphiphilic Pseudo Amino Acid Composition

by Cheng Wang, Wenyan Wang, Kun Lu, Jun Zhang, Peng Chen and Bing Wang

Int. J. Mol. Sci. 2020, 21(16), 5694; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165694 - 08 Aug 2020

Cited by 9 | Viewed by 2408

Abstract

The task of drug-target interaction (DTI) prediction plays important roles in drug development. The experimental methods in DTIs are time-consuming, expensive and challenging. To solve these problems, machine learning-based methods are introduced, which are restricted by effective feature extraction and negative sampling. In this work, features with electrotopological state (E-state) fingerprints for drugs and amphiphilic pseudo amino acid composition (APAAC) for target proteins are tested. E-state fingerprints are extracted based on both molecular electronic and topological features with the same metric. APAAC is an extension of amino acid composition (AAC), which is calculated based on hydrophilic and hydrophobic characters to construct sequence order information. Using the combination of these feature pairs, the prediction model is established by support vector machines. In order to enhance the effectiveness of features, a distance-based negative sampling is proposed to obtain reliable negative samples. It is shown that the prediction results of area under curve for Receiver Operating Characteristic (AUC) are above 98.5% for all the three datasets in this work. The comparison of state-of-the-art methods demonstrates the effectiveness and efficiency of proposed method, which will be helpful for further drug development. Full article

(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications 2020)

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Review

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24 pages, 5306 KiB

Open AccessReview

Hotspots in Plasmodium and RBC Receptor-Ligand Interactions: Key Pieces for Inhibiting Malarial Parasite Invasion

by Manuel Alfonso Patarroyo, Jessica Molina-Franky, Marcela Gómez, Gabriela Arévalo-Pinzón and Manuel Elkin Patarroyo

Int. J. Mol. Sci. 2020, 21(13), 4729; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134729 - 02 Jul 2020

Cited by 11 | Viewed by 3869

Abstract

Protein-protein interactions (IPP) play an essential role in practically all biological processes, including those related to microorganism invasion of their host cells. It has been found that a broad repertoire of receptor-ligand interactions takes place in the binding interphase with host cells in malaria, these being vital interactions for successful parasite invasion. Several trials have been conducted for elucidating the molecular interface of interactions between some Plasmodium falciparum and Plasmodium vivax antigens with receptors on erythrocytes and/or reticulocytes. Structural information concerning these complexes is available; however, deeper analysis is required for correlating structural, functional (binding, invasion, and inhibition), and polymorphism data for elucidating new interaction hotspots to which malaria control methods can be directed. This review describes and discusses recent structural and functional details regarding three relevant interactions during erythrocyte invasion: Duffy-binding protein 1 (DBP1)–Duffy antigen receptor for chemokines (DARC); reticulocyte-binding protein homolog 5 (PfRh5)-basigin, and erythrocyte binding antigen 175 (EBA175)-glycophorin A (GPA). Full article

(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications 2020)

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