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

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 January 2020) | Viewed by 58826

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Alexandre G. De Brevern

E-Mail Website
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

Dear Colleagues,

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

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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

Related Special Issue

Published Papers (15 papers)

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Research

16 pages, 4177 KiB  
Article
Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 Immune Checkpoint Interactions
by Eun-Hye Kim, Masuki Kawamoto, Roopa Dharmatti, Eiry Kobatake, Yoshihiro Ito and Hideyuki Miyatake
Int. J. Mol. Sci. 2020, 21(10), 3639; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103639 - 21 May 2020
Cited by 8 | Viewed by 3302
Abstract
Cancer immunotherapy has been revolutionized by the development of monoclonal antibodies (mAbs) that inhibit interactions between immune checkpoint molecules, such as programmed cell-death 1 (PD-1), and its ligand PD-L1. However, mAb-based drugs have some drawbacks, including poor tumor penetration and high production costs, [...] Read more.
Cancer immunotherapy has been revolutionized by the development of monoclonal antibodies (mAbs) that inhibit interactions between immune checkpoint molecules, such as programmed cell-death 1 (PD-1), and its ligand PD-L1. However, mAb-based drugs have some drawbacks, including poor tumor penetration and high production costs, which could potentially be overcome by small molecule drugs. BMS-8, one of the potent small molecule drugs, induces homodimerization of PD-L1, thereby inhibiting its binding to PD-1. Our assay system revealed that BMS-8 inhibited the PD-1/PD-L1 interaction with IC50 of 7.2 μM. To improve the IC50 value, we designed and synthesized a small molecule based on the molecular structure of BMS-8 by in silico simulation. As a result, we successfully prepared a biphenyl-conjugated bromotyrosine (X) with IC50 of 1.5 μM, which was about five times improved from BMS-8. We further prepared amino acid conjugates of X (amino-X), to elucidate a correlation between the docking modes of the amino-Xs and IC50 values. The results suggested that the displacement of amino-Xs from the BMS-8 in the pocket of PD-L1 homodimer correlated with IC50 values. This observation provides us a further insight how to derivatize X for better inhibitory effect. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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17 pages, 2962 KiB  
Article
Accurate Representation of Protein-Ligand Structural Diversity in the Protein Data Bank (PDB)
by Nicolas K. Shinada, Peter Schmidtke and Alexandre G. de Brevern
Int. J. Mol. Sci. 2020, 21(6), 2243; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062243 - 24 Mar 2020
Cited by 3 | Viewed by 3567
Abstract
The number of available protein structures in the Protein Data Bank (PDB) has considerably increased in recent years. Thanks to the growth of structures and complexes, numerous large-scale studies have been done in various research areas, e.g., protein–protein, protein–DNA, or in drug discovery. [...] Read more.
The number of available protein structures in the Protein Data Bank (PDB) has considerably increased in recent years. Thanks to the growth of structures and complexes, numerous large-scale studies have been done in various research areas, e.g., protein–protein, protein–DNA, or in drug discovery. While protein redundancy was only simply managed using simple protein sequence identity threshold, the similarity of protein-ligand complexes should also be considered from a structural perspective. Hence, the protein-ligand duplicates in the PDB are widely known, but were never quantitatively assessed, as they are quite complex to analyze and compare. Here, we present a specific clustering of protein-ligand structures to avoid bias found in different studies. The methodology is based on binding site superposition, and a combination of weighted Root Mean Square Deviation (RMSD) assessment and hierarchical clustering. Repeated structures of proteins of interest are highlighted and only representative conformations were conserved for a non-biased view of protein distribution. Three types of cases are described based on the number of distinct conformations identified for each complex. Defining these categories decreases by 3.84-fold the number of complexes, and offers more refined results compared to a protein sequence-based method. Widely distinct conformations were analyzed using normalized B-factors. Furthermore, a non-redundant dataset was generated for future molecular interactions analysis or virtual screening studies. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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16 pages, 1464 KiB  
Article
The Major Cat Allergen Fel d 1 Binds Steroid and Fatty Acid Semiochemicals: A Combined In Silico and In Vitro Study
by Cécile Bienboire-Frosini, Rajesh Durairaj, Paolo Pelosi and Patrick Pageat
Int. J. Mol. Sci. 2020, 21(4), 1365; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041365 - 18 Feb 2020
Cited by 17 | Viewed by 4119
Abstract
The major cat allergen Fel d 1 is a tetrameric glycoprotein of the secretoglobin superfamily. Structural aspects and allergenic properties of this protein have been investigated, but its physiological function remains unclear. Fel d 1 is assumed to bind lipids and steroids like [...] Read more.
The major cat allergen Fel d 1 is a tetrameric glycoprotein of the secretoglobin superfamily. Structural aspects and allergenic properties of this protein have been investigated, but its physiological function remains unclear. Fel d 1 is assumed to bind lipids and steroids like the mouse androgen-binding protein, which is involved in chemical communication, either as a semiochemical carrier or a semiochemical itself. This study focused on the binding activity of a recombinant model of Fel d 1 (rFel d 1) towards semiochemical analogs, i.e., fatty acids and steroids, using both in silico calculations and fluorescence measurements. In silico analyses were first adopted to model the interactions of potential ligands, which were then tested in binding assays using the fluorescent reporter N-phenyl-1-naphthylamine. Good ligands were fatty acids, such as the lauric, oleic, linoleic, and myristic fatty acids, as well as steroids like androstenone, pregnenolone, and progesterone, that were predicted by in silico molecular models to bind into the central and surface cavities of rFel d 1, respectively. The lowest dissociation constants were shown by lauric acid (2.6 µM) and androstenone (2.4 µM). The specific affinity of rFel d 1 to semiochemicals supports a function of the protein in cat’s chemical communication, and highlights a putative role of secretoglobins in protein semiochemistry. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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12 pages, 2203 KiB  
Article
Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic Simulations
by Pavel Polishchuk, Alina Kutlushina, Dayana Bashirova, Olena Mokshyna and Timur Madzhidov
Int. J. Mol. Sci. 2019, 20(23), 5834; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235834 - 20 Nov 2019
Cited by 14 | Viewed by 5546
Abstract
Pharmacophore models are widely used for the identification of promising primary hits in compound large libraries. Recent studies have demonstrated that pharmacophores retrieved from protein-ligand molecular dynamic trajectories outperform pharmacophores retrieved from a single crystal complex structure. However, the number of retrieved pharmacophores [...] Read more.
Pharmacophore models are widely used for the identification of promising primary hits in compound large libraries. Recent studies have demonstrated that pharmacophores retrieved from protein-ligand molecular dynamic trajectories outperform pharmacophores retrieved from a single crystal complex structure. However, the number of retrieved pharmacophores can be enormous, thus, making it computationally inefficient to use all of them for virtual screening. In this study, we proposed selection of distinct representative pharmacophores by the removal of pharmacophores with identical three-dimensional (3D) pharmacophore hashes. We also proposed a new conformer coverage approach in order to rank compounds using all representative pharmacophores. Our results for four cyclin-dependent kinase 2 (CDK2) complexes with different ligands demonstrated that the proposed selection and ranking approaches outperformed the previously described common hits approach. We also demonstrated that ranking, based on averaged predicted scores obtained from different complexes, can outperform ranking based on scores from an individual complex. All developments were implemented in open-source software pharmd. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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21 pages, 6466 KiB  
Article
Degradation of High Energy Materials Using Biological Reduction: A Rational Way to Reach Bioremediation
by Stephanie Aguero and Raphaël Terreux
Int. J. Mol. Sci. 2019, 20(22), 5556; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225556 - 07 Nov 2019
Cited by 4 | Viewed by 2764
Abstract
Explosives molecules have been widely used since World War II, leading to considerable contamination of soil and groundwater. Recently, bioremediation has emerged as an environmentally friendly approach to solve such contamination issues. However, the 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX) explosive, which has very low solubility in [...] Read more.
Explosives molecules have been widely used since World War II, leading to considerable contamination of soil and groundwater. Recently, bioremediation has emerged as an environmentally friendly approach to solve such contamination issues. However, the 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX) explosive, which has very low solubility in water, does not provide satisfying results with this approach. In this study, we used a rational design strategy for improving the specificity of the nitroreductase from E. Cloacae (PDB ID 5J8G) toward HMX. We used the Coupled Moves algorithm from Rosetta to redesign the active site around HMX. Molecular Dynamics (MD) simulations and affinity calculations allowed us to study the newly designed protein. Five mutations were performed. The designed nitroreductase has a better fit with HMX. We observed more H-bonds, which productively stabilized the HMX molecule for the mutant than for the wild type enzyme. Thus, HMX’s nitro groups are close enough to the reductive cofactor to enable a hydride transfer. Also, the HMX affinity for the designed enzyme is better than for the wild type. These results are encouraging. However, the total reduction reaction implies numerous HMX derivatives, and each of them has to be tested to check how far the reaction can’ go. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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17 pages, 1327 KiB  
Article
DockNmine, a Web Portal to Assemble and Analyse Virtual and Experimental Interaction Data
by Ennys Gheyouche, Romain Launay, Jean Lethiec, Antoine Labeeuw, Caroline Roze, Alan Amossé and Stéphane Téletchéa
Int. J. Mol. Sci. 2019, 20(20), 5062; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205062 - 12 Oct 2019
Cited by 6 | Viewed by 3581
Abstract
Scientists have to perform multiple experiments producing qualitative and quantitative data to determine if a compound is able to bind to a given target. Due to the large diversity of the potential ligand chemical space, the possibility of experimentally exploring a lot of [...] Read more.
Scientists have to perform multiple experiments producing qualitative and quantitative data to determine if a compound is able to bind to a given target. Due to the large diversity of the potential ligand chemical space, the possibility of experimentally exploring a lot of compounds on a target rapidly becomes out of reach. Scientists therefore need to use virtual screening methods to determine the putative binding mode of ligands on a protein and then post-process the raw docking experiments with a dedicated scoring function in relation with experimental data. Two of the major difficulties for comparing docking predictions with experiments mostly come from the lack of transferability of experimental data and the lack of standardisation in molecule names. Although large portals like PubChem or ChEMBL are available for general purpose, there is no service allowing a formal expert annotation of both experimental data and docking studies. To address these issues, researchers build their own collection of data in flat files, often in spreadsheets, with limited possibilities of extensive annotations or standardisation of ligand descriptions allowing cross-database retrieval. We have conceived the dockNmine platform to provide a service allowing an expert and authenticated annotation of ligands and targets. First, this portal allows a scientist to incorporate controlled information in the database using reference identifiers for the protein (Uniprot ID) and the ligand (SMILES description), the data and the publication associated to it. Second, it allows the incorporation of docking experiments using forms that automatically parse useful parameters and results. Last, the web interface provides a lot of pre-computed outputs to assess the degree of correlations between docking experiments and experimental data. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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24 pages, 4617 KiB  
Article
Analysis of Procollagen C-Proteinase Enhancer-1/Glycosaminoglycan Binding Sites and of the Potential Role of Calcium Ions in the Interaction
by Jan Potthoff, Krzysztof K. Bojarski, Gergely Kohut, Agnieszka G. Lipska, Adam Liwo, Efrat Kessler, Sylvie Ricard-Blum and Sergey A. Samsonov
Int. J. Mol. Sci. 2019, 20(20), 5021; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205021 - 10 Oct 2019
Cited by 12 | Viewed by 3277
Abstract
In this study, we characterize the interactions between the extracellular matrix protein, procollagen C-proteinase enhancer-1 (PCPE-1), and glycosaminoglycans (GAGs), which are linear anionic periodic polysaccharides. We applied molecular modeling approaches to build a structural model of full-length PCPE-1, which is not experimentally available, [...] Read more.
In this study, we characterize the interactions between the extracellular matrix protein, procollagen C-proteinase enhancer-1 (PCPE-1), and glycosaminoglycans (GAGs), which are linear anionic periodic polysaccharides. We applied molecular modeling approaches to build a structural model of full-length PCPE-1, which is not experimentally available, to predict GAG binding poses for various GAG lengths, types and sulfation patterns, and to determine the effect of calcium ions on the binding. The computational data are analyzed and discussed in the context of the experimental results previously obtained using surface plasmon resonance binding assays. We also provide experimental data on PCPE-1/GAG interactions obtained using inhibition assays with GAG oligosaccharides ranging from disaccharides to octadecasaccharides. Our results predict the localization of GAG-binding sites at the amino acid residue level onto PCPE-1 and is the first attempt to describe the effects of ions on protein-GAG binding using modeling approaches. In addition, this study allows us to get deeper insights into the in silico methodology challenges and limitations when applied to GAG-protein interactions. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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19 pages, 7488 KiB  
Article
Application of the Movable Type Free Energy Method to the Caspase-Inhibitor Binding Affinity Study
by Song Xue, Hao Liu and Zheng Zheng
Int. J. Mol. Sci. 2019, 20(19), 4850; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194850 - 29 Sep 2019
Cited by 1 | Viewed by 2618
Abstract
Many studies have provided evidence suggesting that caspases not only contribute to the neurodegeneration associated with Alzheimer’s disease (AD) but also play essential roles in promoting the underlying pathology of this disease. Studies regarding the caspase inhibition draw researchers’ attention through time due [...] Read more.
Many studies have provided evidence suggesting that caspases not only contribute to the neurodegeneration associated with Alzheimer’s disease (AD) but also play essential roles in promoting the underlying pathology of this disease. Studies regarding the caspase inhibition draw researchers’ attention through time due to its therapeutic value in the treatment of AD. In this work, we apply the “Movable Type” (MT) free energy method, a Monte Carlo sampling method extrapolating the binding free energy by simulating the partition functions for both free-state and bound-state protein and ligand configurations, to the caspase-inhibitor binding affinity study. Two test benchmarks are introduced to examine the robustness and sensitivity of the MT method concerning the caspase inhibition complexing. The first benchmark employs a large-scale test set including more than a hundred active inhibitors binding to caspase-3. The second benchmark includes several smaller test sets studying the relative binding free energy differences for minor structural changes at the caspase-inhibitor interaction interfaces. Calculation results show that the RMS errors for all test sets are below 1.5 kcal/mol compared to the experimental binding affinity values, demonstrating good performance in simulating the caspase-inhibitor complexing. For better understanding the protein-ligand interaction mechanism, we then take a closer look at the global minimum binding modes and free-state ligand conformations to study two pairs of caspase-inhibitor complexes with (1) different caspase targets binding to the same inhibitor, and (2) different polypeptide inhibitors targeting the same caspase target. By comparing the contact maps at the binding site of different complexes, we revealed how small structural changes affect the caspase-inhibitor interaction energies. Overall, this work provides a new free energy approach for studying the caspase inhibition, with structural insight revealed for both free-state and bound-state molecular configurations. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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16 pages, 2993 KiB  
Article
Investigation of Phospholipase Cγ1 Interaction with SLP76 Using Molecular Modeling Methods for Identifying Novel Inhibitors
by Neha Tripathi, Iyanar Vetrivel, Stéphane Téletchéa, Mickaël Jean, Patrick Legembre and Adèle D. Laurent
Int. J. Mol. Sci. 2019, 20(19), 4721; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194721 - 23 Sep 2019
Cited by 5 | Viewed by 4368
Abstract
The enzyme phospholipase C gamma 1 (PLCγ1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for [...] Read more.
The enzyme phospholipase C gamma 1 (PLCγ1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for drug discovery against PLCγ1. Therefore, for the first time, a combination of various biophysical methods has been employed to shed light on the atomistic interactions between PLCγ1 and its known binding partners. Indeed, molecular modeling of PLCγ1 with SLP76 peptide and with previously reported inhibitors (ritonavir, anethole, daunorubicin, diflunisal, and rosiglitazone) facilitated the identification of the common critical residues (Gln805, Arg806, Asp808, Glu809, Asp825, Gly827, and Trp828) as well as the quantification of their interaction through binding energies calculations. These features are in agreement with previous experimental data. Such an in depth biophysical analysis of each complex provides an opportunity to identify new inhibitors through pharmacophore mapping, molecular docking and MD simulations. From such a systematic procedure, a total of seven compounds emerged as promising inhibitors, all characterized by a strong binding with PLCγ1 and a comparable or higher binding affinity to ritonavir (∆Gbind < −25 kcal/mol), one of the most potent inhibitor reported till now. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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22 pages, 1330 KiB  
Article
A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1
by Kumar Bhaskar Pal, Mukul Mahanti, Hakon Leffler and Ulf J. Nilsson
Int. J. Mol. Sci. 2019, 20(15), 3786; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20153786 - 02 Aug 2019
Cited by 12 | Viewed by 3664
Abstract
Galectins are a family of galactoside-recognizing proteins involved in different galectin-subtype-specific inflammatory and tumor-promoting processes, which motivates the development of inhibitors that are more selective galectin inhibitors than natural ligand fragments. Here, we describe the synthesis and evaluation of 3-C-methyl-gulopyranoside derivatives [...] Read more.
Galectins are a family of galactoside-recognizing proteins involved in different galectin-subtype-specific inflammatory and tumor-promoting processes, which motivates the development of inhibitors that are more selective galectin inhibitors than natural ligand fragments. Here, we describe the synthesis and evaluation of 3-C-methyl-gulopyranoside derivatives and their evaluation as galectin inhibitors. Methyl 3-deoxy-3-C-(hydroxymethyl)-β-d-gulopyranoside showed 7-fold better affinity for galectin-1 than the natural monosaccharide fragment analog methyl β-d-galactopyranoside, as well as a high selectivity over galectin-2, 3, 4, 7, 8, and 9. Derivatization of the 3-C-hydroxymethyl into amides gave gulosides with improved selectivities and affinities; methyl 3-deoxy-3-C-(methyl-2,3,4,5,6-pentafluorobenzamide)-β-d-gulopyranoside had Kd 700 µM for galectin-1, while not binding any other galectin. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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14 pages, 3526 KiB  
Article
NMR Fragment-Based Screening against Tandem RNA Recognition Motifs of TDP-43
by Gilbert Nshogoza, Yaqian Liu, Jia Gao, Mingqing Liu, Sayed Ala Moududee, Rongsheng Ma, Fudong Li, Jiahai Zhang, Jihui Wu, Yunyu Shi and Ke Ruan
Int. J. Mol. Sci. 2019, 20(13), 3230; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133230 - 30 Jun 2019
Cited by 8 | Viewed by 4355
Abstract
The TDP-43 is originally a nuclear protein but translocates to the cytoplasm in the pathological condition. TDP-43, as an RNA-binding protein, consists of two RNA Recognition Motifs (RRM1 and RRM2). RRMs are known to involve both protein-nucleotide and protein-protein interactions and mediate the [...] Read more.
The TDP-43 is originally a nuclear protein but translocates to the cytoplasm in the pathological condition. TDP-43, as an RNA-binding protein, consists of two RNA Recognition Motifs (RRM1 and RRM2). RRMs are known to involve both protein-nucleotide and protein-protein interactions and mediate the formation of stress granules. Thus, they assist the entire TDP-43 protein with participating in neurodegenerative and cancer diseases. Consequently, they are potential therapeutic targets. Protein-observed and ligand-observed nuclear magnetic resonance (NMR) spectroscopy were used to uncover the small molecule inhibitors against the tandem RRM of TDP-43. We identified three hits weakly binding the tandem RRMs using the ligand-observed NMR fragment-based screening. The binding topology of these hits is then depicted by chemical shift perturbations (CSP) of the 15N-labeled tandem RRM and RRM2, respectively, and modeled by the CSP-guided High Ambiguity Driven biomolecular DOCKing (HADDOCK). These hits mainly bind to the RRM2 domain, which suggests the druggability of the RRM2 domain of TDP-43. These hits also facilitate further studies regarding the hit-to-lead evolution against the TDP-43 RRM domain. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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17 pages, 5502 KiB  
Article
3D-PP: A Tool for Discovering Conserved Three-Dimensional Protein Patterns
by Alejandro Valdés-Jiménez, Josep-L. Larriba-Pey, Gabriel Núñez-Vivanco and Miguel Reyes-Parada
Int. J. Mol. Sci. 2019, 20(13), 3174; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133174 - 28 Jun 2019
Cited by 4 | Viewed by 3967
Abstract
Discovering conserved three-dimensional (3D) patterns among protein structures may provide valuable insights into protein classification, functional annotations or the rational design of multi-target drugs. Thus, several computational tools have been developed to discover and compare protein 3D-patterns. However, most of them only consider [...] Read more.
Discovering conserved three-dimensional (3D) patterns among protein structures may provide valuable insights into protein classification, functional annotations or the rational design of multi-target drugs. Thus, several computational tools have been developed to discover and compare protein 3D-patterns. However, most of them only consider previously known 3D-patterns such as orthosteric binding sites or structural motifs. This fact makes necessary the development of new methods for the identification of all possible 3D-patterns that exist in protein structures (allosteric sites, enzyme-cofactor interaction motifs, among others). In this work, we present 3D-PP, a new free access web server for the discovery and recognition all similar 3D amino acid patterns among a set of proteins structures (independent of their sequence similarity). This new tool does not require any previous structural knowledge about ligands, and all data are organized in a high-performance graph database. The input can be a text file with the PDB access codes or a zip file of PDB coordinates regardless of the origin of the structural data: X-ray crystallographic experiments or in silico homology modeling. The results are presented as lists of sequence patterns that can be further analyzed within the web page. We tested the accuracy and suitability of 3D-PP using two sets of proteins coming from the Protein Data Bank: (a) Zinc finger containing and (b) Serotonin target proteins. We also evaluated its usefulness for the discovering of new 3D-patterns, using a set of protein structures coming from in silico homology modeling methodologies, all of which are overexpressed in different types of cancer. Results indicate that 3D-PP is a reliable, flexible and friendly-user tool to identify conserved structural motifs, which could be relevant to improve the knowledge about protein function or classification. The web server can be freely utilized at https://appsbio.utalca.cl/3d-pp/. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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18 pages, 4689 KiB  
Article
In Silico Study of the Resistance to Organophosphorus Pesticides Associated with Point Mutations in Acetylcholinesterase of Lepidoptera: B. mandarina, B. mori, C. auricilius, C. suppressalis, C. pomonella, H. armígera, P. xylostella, S. frugiperda, and S. litura
by Francisco Reyes-Espinosa, Domingo Méndez-Álvarez, Miguel A. Pérez-Rodríguez, Verónica Herrera-Mayorga, Alfredo Juárez-Saldivar, María A. Cruz-Hernández and Gildardo Rivera
Int. J. Mol. Sci. 2019, 20(10), 2404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102404 - 15 May 2019
Cited by 5 | Viewed by 3686
Abstract
An in silico analysis of the interaction between the complex-ligands of nine acetylcholinesterase (AChE) structures of Lepidopteran organisms and 43 organophosphorus (OPs) pesticides with previous resistance reports was carried out. To predict the potential resistance by structural modifications in Lepidoptera insects, due to [...] Read more.
An in silico analysis of the interaction between the complex-ligands of nine acetylcholinesterase (AChE) structures of Lepidopteran organisms and 43 organophosphorus (OPs) pesticides with previous resistance reports was carried out. To predict the potential resistance by structural modifications in Lepidoptera insects, due to proposed point mutations in AChE, a broad analysis was performed using computational tools, such as homology modeling and molecular docking. Two relevant findings were revealed: (1) Docking results give a configuration of the most probable spatial orientation of two interacting molecules (AChE enzyme and OP pesticide) and (2) a predicted ΔGb. The mutations evaluated in the form 1 acetylcholinesterase (AChE-1) and form 2 acetylcholinesterase (AChE-2) structures of enzymes do not affect in any way (there is no regularity of change or significant deviations) the values of the binding energy (ΔGb) recorded in the AChE–OPs complexes. However, the mutations analyzed in AChE are associated with a structural modification that causes an inadequate interaction to complete the phosphorylation of the enzyme. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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16 pages, 2314 KiB  
Article
Enhancement of Binding Affinity of Folate to Its Receptor by Peptide Conjugation
by Roopa Dharmatti, Hideyuki Miyatake, Avanashiappan Nandakumar, Motoki Ueda, Kenya Kobayashi, Daisuke Kiga, Masayuki Yamamura and Yoshihiro Ito
Int. J. Mol. Sci. 2019, 20(9), 2152; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092152 - 30 Apr 2019
Cited by 10 | Viewed by 5550
Abstract
(1) Background: The folate receptor (FR) is a target for cancer treatment and detection. Expression of the FR is restricted in normal cells but overexpressed in many types of tumors. Folate was conjugated with peptides for enhancing binding affinity to the FR. (2) [...] Read more.
(1) Background: The folate receptor (FR) is a target for cancer treatment and detection. Expression of the FR is restricted in normal cells but overexpressed in many types of tumors. Folate was conjugated with peptides for enhancing binding affinity to the FR. (2) Materials and Methods: For conjugation, folate was coupled with propargyl or dibenzocyclooctyne, and 4-azidophenylalanine was introduced in peptides for “click” reactions. We measured binding kinetics including the rate constants of association (ka) and dissociation (kd) of folate-peptide conjugates with purified FR by biolayer interferometry. After optimization of the conditions for the click reaction, we successfully conjugated folate with designed peptides. (3) Results: The binding affinity, indicated by the equilibrium dissociation constant (KD), of folate toward the FR was enhanced by peptide conjugation. The enhanced FR binding affinity by peptide conjugation is a result of an increase in the number of interaction sites. (4) Conclusion: Such peptide-ligand conjugates will be important in the design of ligands with higher affinity. These high affinity ligands can be useful for targeted drug delivery system. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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Article
Insight into Structural Characteristics of Protein-Substrate Interaction in Pimaricin Thioesterase
by Shuobing Fan, Rufan Wang, Chen Li, Linquan Bai, Yi-Lei Zhao and Ting Shi
Int. J. Mol. Sci. 2019, 20(4), 877; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040877 - 18 Feb 2019
Cited by 2 | Viewed by 3123
Abstract
As a polyene antibiotic of great pharmaceutical significance, pimaricin has been extensively studied to enhance its productivity and effectiveness. In our previous studies, pre-reaction state (PRS) has been validated as one of the significant conformational categories before macrocyclization, and is critical to mutual [...] Read more.
As a polyene antibiotic of great pharmaceutical significance, pimaricin has been extensively studied to enhance its productivity and effectiveness. In our previous studies, pre-reaction state (PRS) has been validated as one of the significant conformational categories before macrocyclization, and is critical to mutual recognition and catalytic preparation in thioesterase (TE)-catalyzed systems. In our study, molecular dynamics (MD) simulations were conducted on pimaricin TE-polyketide complex and PRS, as well as pre-organization state (POS), a molecular conformation possessing a pivotal intra-molecular hydrogen bond, were detected. Conformational transition between POS and PRS was observed in one of the simulations, and POS was calculated to be energetically more stable than PRS by 4.58 kcal/mol. The structural characteristics of PRS and POS-based hydrogen-bonding, and hydrophobic interactions were uncovered, and additional simulations were carried out to rationalize the functions of several key residues (Q29, M210, and R186). Binding energies, obtained from MM/PBSA calculations, were further decomposed to residues, in order to reveal their roles in product release. Our study advanced a comprehensive understanding of pimaricin TE-catalyzed macrocyclization from the perspectives of conformational change, protein-polyketide recognition, and product release, and provided potential residues for rational modification of pimaricin TE. Full article
(This article belongs to the Special Issue Recent Developments on Protein–Ligand Interactions: From Structure, Function to Applications)
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