Pathway and mechanism of drug binding to chemokine receptors revealed by accelerated molecular simulations

Background: Chemokine GPCRs play key roles in biology and medicine. Particularly, CXCR4 promotes cancer metastasis and facilitate HIV entry into host cells. Plerixafor (PLX) is a CXCR4 drug, but the pathway and binding site of PLX in CXCR4 remain unknown. Results & methodology: We have performed molecular docking and all-atom simulations using Gaussian accelerated molecular dynamics (GaMD), which are consistent with previous mutation experiments, suggesting that PLX binds to the orthosteric site of CXCR4 as an antagonist. The GaMD simulations further revealed an intermediate allosteric binding site at the extracellular mouth of CXCR4. Conclusion: The newly identified allosteric site can be targeted for novel drug design targeting CXCR4 and other chemokine receptors.

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Structural basis for subtype-specific inhibition of the P2X7 receptor

eLife ◽

10.7554/elife.22153 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 94

Author(s):

Akira Karasawa ◽

Toshimitsu Kawate

Keyword(s):

P2x7 Receptor ◽

Hydrophobic Interactions ◽

Binding Pocket ◽

Drug Binding ◽

Structural Basis ◽

Atp Binding ◽

Allosteric Site ◽

Channel Opening ◽

A Site ◽

Novel Drug

The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.

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Faculty Opinions recommendation of Computational sampling of a cryptic drug binding site in a protein receptor: explicit solvent molecular dynamics and inhibitor docking to p38 MAP kinase.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1090718.544029 ◽

2007 ◽

Author(s):

Zelda R Wasserman

Keyword(s):

Molecular Dynamics ◽

Map Kinase ◽

Binding Site ◽

P38 Map Kinase ◽

Drug Binding ◽

Drug Binding Site ◽

Protein Receptor ◽

Explicit Solvent

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Structural basis for ligand modulation of the CCR2 conformational landscape

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814131116 ◽

2019 ◽

Vol 116 (17) ◽

pp. 8131-8136 ◽

Cited By ~ 8

Author(s):

Bryn C. Taylor ◽

Christopher T. Lee ◽

Rommie E. Amaro

Keyword(s):

Chemokine Receptor ◽

Chemokine Receptors ◽

Drug Targets ◽

Control Cell ◽

Binding Pocket ◽

Drug Binding ◽

Structural Basis ◽

Allosteric Site ◽

Cc Chemokine ◽

Wide Range

CC chemokine receptor 2 (CCR2) is a part of the chemokine receptor family, an important class of therapeutic targets. These class A G-protein coupled receptors (GPCRs) are involved in mammalian signaling pathways and control cell migration toward endogenous CC chemokine ligands, named for the adjacent cysteine motif on their N terminus. Chemokine receptors and their associated ligands are involved in a wide range of diseases and thus have become important drug targets. CCR2, in particular, promotes the metastasis of cancer cells and is also implicated in autoimmunity-driven type-1 diabetes, diabetic nephropathy, multiple sclerosis, asthma, atherosclerosis, neuropathic pain, and rheumatoid arthritis. Although promising, CCR2 antagonists have been largely unsuccessful to date. Here, we investigate the effect of an orthosteric and an allosteric antagonist on CCR2 dynamics by coupling long-timescale molecular dynamics simulations with Markov-state model theory. We find that the antagonists shift CCR2 into several stable inactive conformations that are distinct from the crystal structure conformation and disrupt a continuous internal water and sodium ion pathway, preventing transitions to an active-like state. Several metastable conformations present a cryptic drug-binding pocket near the allosteric site that may be amenable to targeting with small molecules. Without antagonists, the apo dynamics reveal intermediate conformations along the activation pathway that provide insight into the basal dynamics of CCR2 and may also be useful for future drug design.

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Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor

Quarterly Reviews of Biophysics ◽

10.1017/s0033583515000153 ◽

2015 ◽

Vol 48 (4) ◽

pp. 479-487 ◽

Cited By ~ 83

Author(s):

Kalli Kappel ◽

Yinglong Miao ◽

J. Andrew McCammon

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Binding Site ◽

G Protein ◽

Partial Agonist ◽

Md Simulations ◽

G Protein Coupled Receptor ◽

Accelerated Molecular Dynamics ◽

Dynamics Simulations ◽

G Protein Coupled

AbstractElucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein–ligand binding, especially the drug recognition of GPCRs.

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Mode of inhibitory binding of epigallocatechin gallate to the ubiquitin-activating enzyme Uba1 via accelerated molecular dynamics

RSC Advances ◽

10.1039/d0ra09847g ◽

2021 ◽

Vol 11 (14) ◽

pp. 8264-8276

Author(s):

Paras Gaur ◽

Gabriel Fenteany ◽

Chetna Tyagi

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Binding Site ◽

Bond Formation ◽

Epigallocatechin Gallate ◽

Accelerated Molecular Dynamics ◽

Ubiquitin Binding ◽

Thioester Bond

The hinge-like movement of the SCCH domain upon ligand binding closes the ubiquitin binding site and disrupts the interfaces crucial for thioester bond formation.

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Crystal structure of equine serum albumin in complex with cetirizine reveals a novel drug binding site

Molecular Immunology ◽

10.1016/j.molimm.2016.02.003 ◽

2016 ◽

Vol 71 ◽

pp. 143-151 ◽

Cited By ~ 14

Author(s):

Katarzyna B. Handing ◽

Ivan G. Shabalin ◽

Karol Szlachta ◽

Karolina A. Majorek ◽

Wladek Minor

Keyword(s):

Crystal Structure ◽

Serum Albumin ◽

Binding Site ◽

Drug Binding ◽

Drug Binding Site ◽

Novel Drug

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Computational Sampling of a Cryptic Drug Binding Site in a Protein Receptor: Explicit Solvent Molecular Dynamics and Inhibitor Docking to p38 MAP Kinase

Journal of Molecular Biology ◽

10.1016/j.jmb.2006.03.021 ◽

2006 ◽

Vol 359 (1) ◽

pp. 202-214 ◽

Cited By ~ 68

Author(s):

Tamara Frembgen-Kesner ◽

Adrian H. Elcock

Keyword(s):

Molecular Dynamics ◽

Map Kinase ◽

Binding Site ◽

P38 Map Kinase ◽

Drug Binding ◽

Drug Binding Site ◽

Protein Receptor ◽

Explicit Solvent

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Analysis of dynamic characteristics of human serum albumin binding site residues and its effect on azapropazone binding to HSA

10.22541/au.162252128.82574959/v1 ◽

2021 ◽

Author(s):

Amirhossein Saeinia ◽

Seyed Mahdi Alavi ◽

Elmira Vanaki ◽

Mohammad Nazarnejad

Keyword(s):

Molecular Dynamics ◽

Human Serum Albumin ◽

Drug Design ◽

Serum Albumin ◽

Human Serum ◽

Binding Site ◽

Structural Changes ◽

Drug Binding ◽

Dimensional Structure ◽

Wide Range

Background: Human serum albumin (HSA) is the most abundant protein in the circulatory system compared to other proteins and has been analyzed in a wide range of studies. In this research, molecular dynamics and docking of HSA with azapropazone have been simulated. Methods: The three-dimensional structure of human serum albumin was obtained to simulate molecular dynamics from RCSB. GROMACS was used for molecular dynamic simulations and received 30 frames. Autodock vina was used for docking between HSA and Azapropazone. Results: Based on the obtained results, the residues of Sudlow I junction have structural changes according to their chemical properties. Conclusion: In this study, a new method has been used on HSA compared to previous studies that can be used in drug design research. Understanding the structural and behavioral characteristics of HSA binding site can be a great help in drug design because structural changes in binding amino acids affect drug binding

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Targeting interactions between the Galectin-3 intrinsically disordered and structured domains based on long time-scale accelerated molecular dynamics

10.1101/2021.09.27.461147 ◽

2021 ◽

Author(s):

Supriyo Bhattacharya ◽

Mingfeng Zhang ◽

Weidong Hu ◽

Tong Qi ◽

Nora Heisterkamp

Keyword(s):

Molecular Dynamics ◽

Drug Development ◽

Md Simulations ◽

Drug Binding ◽

Carbohydrate Binding ◽

Accelerated Molecular Dynamics ◽

Intrinsically Disordered ◽

Terminal Domain ◽

Binding Interface ◽

Galectin 3

Intrinsically disordered regions (IDRs) are common and important functional domains in many proteins. However, IDRs are difficult to target for drug development due to the lack of defined structures which would facilitate the identification of possible drug-binding pockets. Galectin-3 is a carbohydrate-binding protein of which overexpression has been implicated in a wide variety of disorders including cancer and inflammation. Apart from its carbohydrate recognition/binding domain (CRD), Galectin-3 also contains a functionally important disordered N-terminal domain (NTD) that contacts the C-terminal domain (CTD) and could be a target for drug development. To overcome challenges involved in inhibitor design due to lack of structure and the highly dynamic nature of the NTD, we used a novel protocol combining nuclear magnetic resonance data from recombinant Galectin-3 with accelerated molecular dynamics (MD) simulations to identify a shallow pocket in the CTD with which the NTD makes frequent contact. In accordance with this model, a Galectin-3 double mutant of residues L131 and L203 in the CTD lost agglutination ability. In-silico design was used to narrow down candidate inhibitory peptides and experimental testing of only 3 of these yielded one peptide that inhibits the agglutination promoted by wild type Galectin-3. NMR experiments further confirmed that this peptide makes contacts with a non-carbohydrate binding moiety of the CTD. Our results show that it is possible to apply a combination of MD simulations and NMR experiments to precisely predict the binding interface of a disordered domain with a structured domain, and furthermore use this predicted interface for designing inhibitors. This procedure can thus be potentially extended to many other targets in which similar IDR interactions play a vital functional role.

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