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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 (28 September 2019) | Viewed by 47764

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Special Issue Editor

Prof. Dr. Roberta Galeazzi

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Guest Editor

Department of Life and Environmental Science (DISVA), Marche Polythecnic University, Ancona, Italy
Interests: computer aided drug design; molecular dynamics simulation of membrane receptors and lipid bilayers; rational drug design; bacterial efflux pumps' inhibitors; computational design of novel nanovectors for drug delivery
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Special Issue Information

Dear Colleagues,

Cellular membranes contain membrane receptors which mediate signal transduction for cellular responses to extracellular stimuli. These receptors are transmembrane proteins, and are classified by structure and related function. They are associated with G-proteins, ion channels, and tyrosin–chinase receptors. The domain of the receptor exposed to the external medium often has a binding site for a ligand. The domain exposed to the cytoplasm activates intracellular proteins such as kinases, G-proteins, guanylate cyclase, ion transporters, among a myriad of other functions.

In this Special Issue, we want to focus on various types of simulation aimed at elucidating the structure and the function of these receptors. In addition, studies related to a rational drug design approach with a membrane receptor as target are welcome.

Potential topics include, without being limited to, the following:

Molecular dynamics simulation of ion channels
Computer aided drug design targeted at membrane receptors
Ligand–receptor dynamics
Function and structure of membrane receptors
Coarse grained molecular dynamics of receptor association and oligomerization

Prof. Dr. Roberta Galeazzi
Guest Editor

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Keywords

Membrane receptors
Molecular dynamics
Molecular docking
Protein–protein association
Rational drug design

Published Papers (11 papers)

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Research

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17 pages, 3272 KiB

Open AccessArticle

Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

by Cristina Minnelli, Emiliano Laudadio, Giovanna Mobbili and Roberta Galeazzi

Int. J. Mol. Sci. 2020, 21(5), 1721; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051721 - 03 Mar 2020

Cited by 32 | Viewed by 4309

Abstract

Non-small cell lung cancer (NSCLC) represents a difficult condition to treat, due to epidermal growth factor receptor (EGFR) kinase domain mutations, which lead to ligand-independent phosphorylation. Deletion of five amino acids (ELREA) in exon 19 and mutational change from leucine to arginine at position 858 (L858R) are responsible for tyrosine kinase domain aberrant activation. These two common types of EGFR-mutated forms are clinically associated with high response with Tyrosine Kinase Inhibitors (TKI); however, the secondary T790M mutation within the Tyrosine Kinase Domain (TKD) determines a resistance to these EGFR-TKIs. Using molecular dynamic simulation (MD), the present study investigated the architectural changes of wild-type and mutants EGFR’s kinase domains in order to detect any conformational differences that could be associated with a constitutively activated state and thus to evaluate the differences between the wild-type and its mutated forms. In addition, in order to evaluate to which extent the EGFR mutations affect its inhibition, Epigallocatechin 3-Gallate (EGCG) and Erlotinib (Erl), known EGFR-TKI, were included in our study. Their binding modes with the EGFR-TK domain were elucidated and the binding differences between EGFR wild-type and the mutated forms were evidenced. The aminoacids mutations directly influence the binding affinity of these two inhibitors, resulting in a different efficacy of Erl and EGCG inhibition. In particular, for the T790M/L858R EGFR, the binding modes of studied inhibitors were compromised by aminoacidic substitution confirming the experimental findings. These results may be useful for novel drug design strategies targeting the dimerization domain of the EGFR mutated forms, thus preventing receptor activation. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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15 pages, 5888 KiB

Open AccessArticle

Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli

by Alessio Atzori, Giuliano Malloci, Francesca Cardamone, Andrea Bosin, Attilio Vittorio Vargiu and Paolo Ruggerone

Int. J. Mol. Sci. 2020, 21(3), 860; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030860 - 29 Jan 2020

Cited by 11 | Viewed by 3191

Abstract

The drug/proton antiporter AcrB, engine of the major efflux pump AcrAB(Z)-TolC of Escherichia coli and other bacteria, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance (MDR) phenotype. Although hundreds of small molecules are known to be AcrB substrates, only a few co-crystal structures are available to date. Computational methods have been therefore intensively employed to provide structural and dynamical fingerprints related to transport and inhibition of AcrB. In this work, we performed a systematic computational investigation to study the interaction between representative carbapenem antibiotics and AcrB. We focused on the interaction of carbapenems with the so-called distal pocket, a region known for its importance in binding inhibitors and substrates of AcrB. Our findings reveal how the different physico-chemical nature of these antibiotics is reflected on their binding preference for AcrB. The molecular-level information provided here could help design new antibiotics less susceptible to the efflux mechanism. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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22 pages, 10517 KiB

Open AccessArticle

Preferential Coupling of Dopamine D_2S and D_2L Receptor Isoforms with G_i1 and G_i2 Proteins—In Silico Study

by Justyna Żuk, Damian Bartuzi, Dariusz Matosiuk and Agnieszka A. Kaczor

Int. J. Mol. Sci. 2020, 21(2), 436; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020436 - 09 Jan 2020

Cited by 12 | Viewed by 3191

Abstract

The dopamine D₂ receptor belongs to rhodopsin-like G protein-coupled receptors (GPCRs) and it is an important molecular target for the treatment of many disorders, including schizophrenia and Parkinson’s disease. Here, computational methods were used to construct the full models of the dopamine D₂ receptor short (D_2S) and long (D_2L) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with G_i1 and G_i2 proteins. It was found that the D_2L isoform preferentially couples with the G_i2 protein and D_2S isoform with the G_i1 protein, which is in accordance with experimental data. Our findings give mechanistic insight into the interplay between isoforms of dopamine D₂ receptors and G_i proteins subtypes, which is important to understand signaling by these receptors and their mediation by pharmaceuticals, in particular psychotic and antipsychotic agents. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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16 pages, 17329 KiB

Open AccessArticle

Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods

by Luis Jaimes Santiago and Ravinder Abrol

Int. J. Mol. Sci. 2019, 20(21), 5290; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215290 - 24 Oct 2019

Cited by 12 | Viewed by 8958

Abstract

The neurotransmitter molecule acetylcholine is capable of activating five muscarinic acetylcholine receptors, M1 through M5, which belong to the superfamily of G-protein-coupled receptors (GPCRs). These five receptors share high sequence and structure homology; however, the M1, M3, and M5 receptor subtypes signal preferentially through the Gαq/11 subset of G proteins, whereas the M2 and M4 receptor subtypes signal through the Gαi/o subset of G proteins, resulting in very different intracellular signaling cascades and physiological effects. The structural basis for this innate ability of the M1/M3/M5 set of receptors and the highly homologous M2/M4 set of receptors to couple to different G proteins is poorly understood. In this study, we used molecular dynamics (MD) simulations coupled with thermodynamic analyses of M1 and M2 receptors coupled to both Gαi and Gαq to understand the structural basis of the M1 receptor’s preference for the Gαq protein and the M2 receptor’s preference for the Gαi protein. The MD studies showed that the M1 and M2 receptors can couple to both Gα proteins such that the M1 receptor engages with the two Gα proteins in slightly different orientations and the M2 receptor engages with the two Gα proteins in the same orientation. Thermodynamic studies of the free energy of binding of the receptors to the Gα proteins showed that the M1 and M2 receptors bind more strongly to their cognate Gα proteins compared to their non-cognate ones, which is in line with previous experimental studies on the M3 receptor. A detailed analysis of receptor–G protein interactions showed some cognate-complex-specific interactions for the M2:Gαi complex; however, G protein selectivity determinants are spread over a large overlapping subset of residues. Conserved interaction between transmembrane helices 5 and 6 far away from the G-protein-binding receptor interface was found only in the two cognate complexes and not in the non-cognate complexes. An analysis of residues implicated previously in G protein selectivity, in light of the cognate and non-cognate structures, shaded a more nuanced role of those residues in affecting G protein selectivity. The simulation of both cognate and non-cognate receptor–G protein complexes fills a structural gap due to difficulties in determining non-cognate complex structures and provides an enhanced framework to probe the mechanisms of G protein selectivity exhibited by most GPCRs. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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10 pages, 980 KiB

Open AccessArticle

The Universal 3D QSAR Model for Dopamine D₂ Receptor Antagonists

by Agata Zięba, Justyna Żuk, Damian Bartuzi, Dariusz Matosiuk, Antti Poso and Agnieszka A. Kaczor

Int. J. Mol. Sci. 2019, 20(18), 4555; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184555 - 14 Sep 2019

Cited by 5 | Viewed by 2857

Abstract

In order to search for novel antipsychotics acting through the D₂ receptor, it is necessary to know the structure–activity relationships for dopamine D₂ receptor antagonists. In this context, we constructed the universal three-dimensional quantitative structure–activity relationship (3D- QSAR) model for competitive dopamine D₂ receptor antagonists. We took 176 compounds from chemically different groups characterized by the half maximal inhibitory concentration (IC₅₀)from the CHEMBL database and docked them to the X-ray structure of the human D₂ receptor in the inactive state. Selected docking poses were applied for Comparative Molecular Field Analysis (CoMFA) alignment. The obtained CoMFA model is characterized by a cross-validated coefficient Q² of 0.76 with an optimal component of 5, R² of 0.92, and an F value of 338.9. The steric and electrostatic field contributions are 67.4% and 32.6%, respectively. The statistics obtained prove that the CoMFA model is significant. Next, the IC₅₀ of the 16 compounds from the test set was predicted with R² of 0.95. Finally, a progressive scrambling test was carried out for additional validation. The CoMFA fields were mapped onto the dopamine D₂ receptor binding site, which enabled a discussion of the structure–activity relationship based on ligand–receptor interactions. In particular, it was found that one of the desired steric interactions covers the area of a putative common allosteric pocket suggested for some other G protein-coupled receptors (GPCRs), which would suggest that some of the known dopamine receptor antagonists are bitopic in their essence. The CoMFA model can be applied to predict the potential activity of novel dopamine D₂ receptor antagonists. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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21 pages, 2809 KiB

Open AccessArticle

A Molecular Dynamics Study of Vasoactive Intestinal Peptide Receptor 1 and the Basis of Its Therapeutic Antagonism

by Dorota Latek, Ingrid Langer, Krystiana A. Krzysko and Lukasz Charzewski

Int. J. Mol. Sci. 2019, 20(18), 4348; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184348 - 05 Sep 2019

Cited by 10 | Viewed by 3413

Abstract

Vasoactive intestinal peptide receptor 1 (VPAC1) is a member of a secretin-like subfamily of G protein-coupled receptors. Its endogenous neuropeptide (VIP), secreted by neurons and immune cells, modulates various physiological functions such as exocrine and endocrine secretions, immune response, smooth muscles relaxation, vasodilation, and fetal development. As a drug target, VPAC1 has been selected for therapy of inflammatory diseases but drug discovery is still hampered by lack of its crystal structure. In this study we presented the homology model of this receptor constructed with the well-known web service GPCRM. The VPAC1 model is composed of extracellular and transmembrane domains that form a complex with an endogenous hormone VIP. Using the homology model of VPAC1 the mechanism of action of potential drug candidates for VPAC1 was described. Only two series of small-molecule antagonists of confirmed biological activity for VPAC1 have been described thus far. Molecular docking and a series of molecular dynamics simulations were performed to elucidate their binding to VPAC1 and resulting antagonist effect. The presented work provides the basis for the possible binding mode of VPAC1 antagonists and determinants of their molecular recognition in the context of other class B GPCRs. Until the crystal structure of VPAC1 will be released, the presented homology model of VPAC1 can serve as a scaffold for drug discovery studies and is available from the author upon request. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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16 pages, 3500 KiB

Open AccessArticle

Deciphering the Molecular Recognition Mechanism of Multidrug Resistance Staphylococcus aureus NorA Efflux Pump Using a Supervised Molecular Dynamics Approach

by Deborah Palazzotti, Maicol Bissaro, Giovanni Bolcato, Andrea Astolfi, Tommaso Felicetti, Stefano Sabatini, Mattia Sturlese, Violetta Cecchetti, Maria Letizia Barreca and Stefano Moro

Int. J. Mol. Sci. 2019, 20(16), 4041; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20164041 - 19 Aug 2019

Cited by 19 | Viewed by 4918

Abstract

The use and misuse of antibiotics has resulted in critical conditions for drug-resistant bacteria emergency, accelerating the development of antimicrobial resistance (AMR). In this context, the co-administration of an antibiotic with a compound able to restore sufficient antibacterial activity may be a successful strategy. In particular, the identification of efflux pump inhibitors (EPIs) holds promise for new antibiotic resistance breakers (ARBs). Indeed, bacterial efflux pumps have a key role in AMR development; for instance, NorA efflux pump contributes to Staphylococcus aureus (S. aureus) resistance against fluoroquinolone antibiotics (e.g., ciprofloxacin) by promoting their active extrusion from the cells. Even though NorA efflux pump is known to be a potential target for EPIs development, the absence of structural information about this protein and the little knowledge available on its mechanism of action have strongly hampered rational drug discovery efforts in this area. In the present work, we investigated at the molecular level the substrate recognition pathway of NorA through a Supervised Molecular Dynamics (SuMD) approach, using a NorA homology model. Specific amino acids were identified as playing a key role in the efflux pump-mediated extrusion of its substrate, paving the way for a deeper understanding of both the mechanisms of action and the inhibition of such efflux pumps. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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12 pages, 2701 KiB

Open AccessArticle

Free-Energy Calculations for Bioisosteric Modifications of A₃ Adenosine Receptor Antagonists

by Zuzana Jandova, Willem Jespers, Eddy Sotelo, Hugo Gutiérrez-de-Terán and Chris Oostenbrink

Int. J. Mol. Sci. 2019, 20(14), 3499; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143499 - 16 Jul 2019

Cited by 2 | Viewed by 2506

Abstract

Adenosine receptors are a family of G protein-coupled receptors with increased attention as drug targets on different indications. We investigate the thermodynamics of ligand binding to the A₃ adenosine receptor subtype, focusing on a recently reported series of diarylacetamidopyridine inhibitors via molecular dynamics simulations. With a combined approach of thermodynamic integration and one-step perturbation, we characterize the impact of the charge distribution in a central heteroaromatic ring on the binding affinity prediction. Standard charge distributions according to the GROMOS force field yield values in good agreement with the experimental data and previous free energy calculations. Subsequently, we examine the thermodynamics of inhibitor binding in terms of the energetic and entropic contributions. The highest entropy penalties are found for inhibitors with methoxy substituents in meta position of the aryl groups. This bulky group restricts rotation of aromatic rings attached to the pyrimidine core which leads to two distinct poses of the ligand. Our predictions support the previously proposed binding pose for the o-methoxy ligand, yielding in this case a very good correlation with the experimentally measured affinities with deviations below 4 kJ/mol. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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18 pages, 18751 KiB

Open AccessArticle

A Metadynamics-Based Protocol for the Determination of GPCR-Ligand Binding Modes

by Christian A. Söldner, Anselm H. C. Horn and Heinrich Sticht

Int. J. Mol. Sci. 2019, 20(8), 1970; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20081970 - 22 Apr 2019

Cited by 18 | Viewed by 4902

Abstract

G protein-coupled receptors (GPCRs) are a main drug target and therefore a hot topic in pharmaceutical research. One important prerequisite to understand how a certain ligand affects a GPCR is precise knowledge about its binding mode and the specific underlying interactions. If no crystal structure of the respective complex is available, computational methods can be used to deduce the binding site. One of them are metadynamics simulations which have the advantage of an enhanced sampling compared to conventional molecular dynamics simulations. However, the enhanced sampling of higher-energy states hampers identification of the preferred binding mode. Here, we present a novel protocol based on clustering of multiple walker metadynamics simulations which allows identifying the preferential binding mode from such conformational ensembles. We tested this strategy for three different model systems namely the histamine H₁ receptor in combination with its physiological ligand histamine, as well as the

β_{2}

adrenoceptor with its agonist adrenaline and its antagonist alprenolol. For all three systems, the proposed protocol was able to reproduce the correct binding mode known from the literature suggesting that the approach can more generally be applied to the prediction of GPCR ligand binding in future. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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18 pages, 2753 KiB

Open AccessArticle

Hydrodynamic and Electrophoretic Properties of Trastuzumab/HER2 Extracellular Domain Complexes as Revealed by Experimental Techniques and Computational Simulations

by Javier Ramos, Juan Francisco Vega, Victor Cruz, Eduardo Sanchez-Sanchez, Javier Cortes and Javier Martinez-Salazar

Int. J. Mol. Sci. 2019, 20(5), 1076; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051076 - 01 Mar 2019

Cited by 6 | Viewed by 3444

Abstract

The combination of hydrodynamic and electrophoretic experiments and computer simulations is a powerful approach to study the interaction between proteins. In this work, we present hydrodynamic and electrophoretic experiments in an aqueous solution along with molecular dynamics and hydrodynamic modeling to monitor and compute biophysical properties of the interactions between the extracellular domain of the HER2 protein (eHER2) and the monoclonal antibody trastuzumab (TZM). The importance of this system relies on the fact that the overexpression of HER2 protein is related with the poor prognosis breast cancers (HER2++ positives), while the TZM is a monoclonal antibody for the treatment of this cancer. We have found and characterized two different complexes between the TZM and eHER2 proteins (1:1 and 1:2 TZM:eHER2 complexes). The conformational features of these complexes regulate their hydrodynamic and electrostatic properties. Thus, the results indicate a high degree of molecular flexibility in the systems that ultimately leads to higher values of the intrinsic viscosity, as well as lower values of diffusion coefficient than those expected for simple globular proteins. A highly asymmetric charge distribution is detected for the monovalent complex (1:1 complex), which has strong implications in correlations between the experimental electrophoretic mobility and the modeled net charge. In order to understand the dynamics of these systems and the role of the specific domains involved, it is essential to find biophysical correlations between dynamics, macroscopic transport and electrostatic properties. The results should be of general interest for researchers working in this area. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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Review

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17 pages, 2582 KiB

Open AccessReview

Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery

by Ye Zou, John Ewalt and Ho-Leung Ng

Int. J. Mol. Sci. 2019, 20(17), 4237; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174237 - 29 Aug 2019

Cited by 22 | Viewed by 5422

Abstract

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. Some ligands that bind to GPCRs activate different downstream signaling pathways. G protein activation, or β-arrestin biased signaling, involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. β-arrestin biased signaling has become a hot target for structure-based drug discovery. However, challenges include that there are few crystal structures available in the Protein Data Bank and that GPCRs are highly dynamic. Hence, molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators’ interactions with receptors and ligands. Here, we highlight recent MD simulation studies and enhanced sampling methods used to study biased G protein-coupled receptor signaling and their conformational dynamics as well as applications to drug discovery. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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