scholarly journals Retrospective Ensemble Docking of Allosteric Modulators in an Adenosine G-Protein-Coupled Receptor

2020 ◽  
Author(s):  
Apurba Bhattarai ◽  
Jinan Wang ◽  
Yinglong Miao
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Ischemia Reperfusion ◽  
Renal Diseases ◽  
Allosteric Modulators ◽  
Receptor Flexibility ◽  
Ensemble Docking ◽  
G Protein Coupled

AbstractBackgroundEnsemble docking has proven useful in drug discovery and development. It increases the hit rate by incorporating receptor flexibility into molecular docking as demonstrated on important drug targets including G-protein-coupled receptors (GPCRs). Adenosine A1 receptor (A1AR) is a key GPCR that has been targeted for treating cardiac ischemia-reperfusion injuries, neuropathic pain and renal diseases. Development of allosteric modulators, compounds binding to distinct and less conserved GPCR target sites compared with agonists and antagonists, has attracted increasing interest for designing selective drugs of the A1AR. Despite significant advances, more effective approaches are needed to discover potent and selective allosteric modulators of the A1AR.MethodsEnsemble docking that integrates Gaussian accelerated molecular dynamic (GaMD) simulations and molecular docking using Autodock has been implemented for retrospective docking of known positive allosteric modulators (PAMs) in the A1AR.ResultsEnsemble docking outperforms docking of the receptor cryo-EM structure. The calculated docking enrichment factors (EFs) and the area under the receiver operating characteristic curves (AUC) are significantly increased.ConclusionsReceptor ensembles generated from GaMD simulations are able to increase the success rate of discovering PAMs of A1AR. It is important to account for receptor flexibility through GaMD simulations and flexible docking.General SignificanceEnsemble docking is a promising approach for drug discovery targeting flexible receptors.

scholarly journals G-Protein-Coupled Receptor-Membrane Interactions Depend on the Receptor Activation state

2019 ◽  
Author(s):  
Apurba Bhattarai ◽  
Jinan Wang ◽  
Yinglong Miao
Keyword(s):  
G Protein ◽  
Lipid Bilayer ◽  
Protein Interactions ◽  
Membrane Lipids ◽  
Ischemia Reperfusion ◽  
Receptor Activation ◽  
Renal Diseases ◽  
Conformational States ◽  
Highly Correlated ◽  
G Protein Coupled

AbstractG-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as primary targets of ∼1/3 of currently marketed drugs. In particular, adenosine A1 receptor (A1AR) is an important therapeutic target for treating cardiac ischemia-reperfusion injuries, neuropathic pain and renal diseases. As a prototypical GPCR, the A1AR is located within a phospholipid membrane bilayer and transmits cellular signals by changing between different conformational states. It is important to elucidate the lipid-protein interactions in order to understand the functional mechanism of GPCRs. Here, all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method were performed on both the inactive (antagonist bound) and active (agonist and G protein bound) A1AR, which was embedded in a 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipid bilayer. In the GaMD simulations, the membrane lipids played a key role in stabilizing different conformational states of the A1AR. Our simulations further identified important regions of the receptor that interacted distinctly with the lipids in highly correlated manner. Activation of the A1AR led to differential dynamics in the upper and lower leaflets of the lipid bilayer. In summary, GaMD enhanced simulations have revealed strongly coupled dynamics of the GPCR and lipids that depend on the receptor activation state.

scholarly journals Insights from Molecular Dynamics Simulations for GPCR Drug Discovery

2019 ◽  
Author(s):  
Ye Zou ◽  
John Ewalt ◽  
Ho-Leung Ng
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Protein Activation ◽  
Downstream Signaling ◽  
Dynamics Simulations ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. There is evidence that some ligands that bind to the GPCRs activate different downstream signaling pathways. G protein activation or -arrestin biased signaling involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. Molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators' interactions between receptors and ligands. Here, we highlight recent simulation studies and methods used to study biased G protein-coupled receptor signaling and their conformational dynamics. We also highlight applications of MD simulations to drug discovery.

scholarly journals Advances in the molecular understanding of G protein-coupled receptors and their future therapeutic opportunities

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Daniel N. Obot ◽  
Godswill J. Udom ◽  
Anwanabasi E. Udoh ◽  
Nkechi J. Onyeukwu ◽  
Ayobami J. Olusola ◽  
...  
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Main Body ◽  
Target Class ◽  
Proper Diagnosis ◽  
Approved Drugs ◽  
G Protein Coupled

Abstract Background Understanding the mechanisms, activated and inhibited pathways as well as other molecular targets involved in existing and emerging disease conditions provides useful insights into their proper diagnosis and treatment and aids drug discovery, development and production. G protein-coupled receptors (GPCRs) are one of the most important classes of targets for small-molecule drug discovery. Of all drug targets, GPCRs are the most studied, undoubtedly because of their pharmacological tractability and role in the pathophysiology as well as the pathogenesis of human diseases. Main body of the abstract GPCRs are regarded as the largest target class of the “druggable genome” representing approximately 19% of the currently available drug targets. They have long played a prominent role in drug discovery, such that as of this writing, 481 drugs (about 34% of all FDA-approved drugs) act on GPCRs. More than 320 therapeutic agents are currently under clinical trials, of which a significant percentage targets novel GPCRs. GPCRs are implicated in a wide variety of diseases including CNS disorders, inflammatory diseases such as rheumatoid arthritis and Crohn’s disease, as well as metabolic disease and cancer. The non-olfactory human GPCRs yet to be clinically explored or tried are endowed with perhaps a huge untapped potential drug discovery especially in the field of immunology and genetics. Short conclusion This review discusses the recent advances in the molecular pharmacology and future opportunities for targeting GPCRs with a view to drug development.

Improving ensemble docking for drug discovery by machine learning

2019 ◽  
Vol 18 (03) ◽  
pp. 1920001 ◽  
Author(s):  
Chung F. Wong
Keyword(s):  
Machine Learning ◽  
Molecular Docking ◽  
Drug Discovery ◽  
Inexpensive Method ◽  
Receptor Flexibility ◽  
Ensemble Docking ◽  
Ensemble Machine Learning ◽  
Multiple Structures

Ensemble docking has provided an inexpensive method to account for receptor flexibility in molecular docking. However, it is still unclear how best to use the docking scores from multiple structures to classify compounds into actives and inactives. Previous studies have also found that the performance of classification could decrease rather than increase with the number of structures included in the ensemble. Machine learning could help to alleviate these problems.

Efficiency of Homology Modeling assisted Molecular Docking in G-protein coupled receptors

2020 ◽  
Vol 20 ◽  
Author(s):  
Shome S. Bhunia ◽  
Anil K. Saxena
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Homology Modeling ◽  
Crystal Structures ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Protein Crystal ◽  
Protein Crystal Structure ◽  
Rational Drug ◽  
G Protein Coupled

Background: Molecular docking is in regular practice to assess ligand affinity on a target protein crystal structure. In absence of protein crystal structure, the homology modeling or comparative modeling is the best alternative to elucidate the relationship details between a ligand and protein at the molecular level. The development of accurate homology modeling (HM) and its integration with molecular docking (MD) is essential for successful, rational drug discovery. Objective: The G-protein coupled receptors (GPCRs) are attractive therapeutic targets due to their immense role in human pharmacology. The GPCRs are membrane bound proteins with complex constitution and the understanding of their activation and inactivation mechanisms is quite challenging. Over the past decade there has been a rapid expansion in the number of solved G-protein-coupled receptor (GPCR) crystal structures however majority of the GPCR structures remain unsolved. In this context HM guided MD has been widely used for structure-based drug design (SBDD) of GPCRs. Methods: The focus of this review is on the recent (i) developments on HM supported GPCR drug discovery in absence of GPCR crystal structures (ii) application of HM in understanding the ligand interactions at the binding site, virtual screening, determining receptor sub type selectivity and receptor behaviour in comparison with GPCR crystal structures . Results: The HM in GPCRs has been extremely challenging due to the scarcity in template structures. In such a scenario it is difficult to get accurate HM that can facilitate understanding of the ligand-receptor interactions. This problem has been alleviated to some extent by developing refined HM based on incorporating active /inactive ligand information and inducing protein flexibility. In some cases HM proteins were found to outscore crystal structures also. Conclusion: The developments in HM have been highly operative to gain insights about the ligand interaction at the binding site and receptor functioning at molecular level. Thus HM guided molecular docking may be useful for rational drug discovery for the GPCRs mediated diseases.

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

2019 ◽  
Vol 20 (17) ◽  
pp. 4237 ◽  
Author(s):  
Zou ◽  
Ewalt ◽  
Ng
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Data Bank ◽  
G Protein Coupled Receptor ◽  
Biased Signaling ◽  
G Protein Coupled

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 -arrestin biased signaling, involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. -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.

scholarly journals Natural Compounds as Guides for the Discovery of Drugs Targeting G-Protein-Coupled Receptors

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5060
Author(s):  
Joan Serrano-Marín ◽  
Irene Reyes-Resina ◽  
Eva Martínez-Pinilla ◽  
Gemma Navarro ◽  
Rafael Franco
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
G Protein ◽  
Natural Compounds ◽  
G Protein Coupled Receptors ◽  
Taste Receptors ◽  
Allosteric Modulators ◽  
Chemical Structures ◽  
Therapeutic Drugs ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs), which constitute the most populous family of the human proteome, are the target of 35–45% of approved therapeutic drugs. This review focuses on natural products (excluding peptides) that target GPCRs. Natural compounds identified so far as agonists, antagonists or allosteric modulators of GPCRs have been found in all groups of existing living beings according to Whittaker’s Five Kingdom Classification, i.e., bacteria (monera), fungi, protoctists, plants and animals. Terpenoids, alkaloids and flavonoids are the most common chemical structures that target GPCRs whose endogenous ligands range from lipids to epinephrine, from molecules that activate taste receptors to molecules that activate smell receptors. Virtually all of the compounds whose formula is displayed in this review are pharmacophores with potential for drug discovery; furthermore, they are expected to help expand the number of GPCRs that can be considered as therapeutic targets.

scholarly journals G Protein-coupled Receptors: One of the Most Important Drug Discovery Targets

2018 ◽  
Vol 25 (2) ◽  
pp. 27-35
Author(s):  
Yusra Saleh Andijani
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Allosteric Modulators ◽  
Biased Agonism ◽  
The Central Nervous System ◽  
Almost All ◽  
Complex Signaling ◽  
G Protein Coupled

G protein-coupled receptors are considered the most widely investigated drug discovery targets. They are the largest family of receptors with almost 800 genes in humans. Different types of ligands can activate these receptors, such as catecholamines, nucleotides, lipids, and gut microbiota, where some ligands could be bitopic. Nevertheless, some receptors have internal ligands bound to them. Activated G protein-coupled receptors have complex signaling pathways that are involved in almost all bodily functions. Furthermore, they constitute a large percentage of Food and Drug Administration marketed drugs and global share of drugs, in addition to a great proportion of drugs currently in clinical trials targeting these receptors. The approved G protein-coupled receptors targeted drugs and potential drugs are involved in the management of many diseases including cancer, inflammatory diseases, diabetes mellitus, hypertension, obesity, pain, and diseases of the central nervous system. Only 10% of G protein-coupled receptors are targeted. Different pharmacological approaches have been considered in drug discovery of these receptors including polypharmacology, allosteric modulators, biased agonism, tethered agonism, and pharmacogenomics. Advances in the technologies are promising to help in the discovery of new targets. The review's aim is to discuss the importance of G protein-coupled receptors as drug discovery targets.

G-protein-coupled receptor accessory proteins: their potential role in future drug discovery

2004 ◽  
Vol 32 (5) ◽  
pp. 888-891 ◽  
Author(s):  
J. Presland
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Chemical Space ◽  
Receptor Protein ◽  
G Protein Coupled Receptor ◽  
Functional Responses ◽  
Alternative Intervention ◽  
Future Drug ◽  
G Protein Coupled

Historically, the activation and inhibition of GPCR (G-protein-coupled receptor) function have been a very successful avenue for drug discovery and development. However, it is clear that receptors do not function in isolation but are impacted by other proteins. These proteins may alter either binding or functional responses. Identification and study of these interactions have grown rapidly in recent years and continue to do so, resulting in a plethora of potential receptor–protein connections. These associations can be regarded as alternative intervention points to modulate GPCR function and may not only provide alternative ways to modify receptor activity but also to exploit new chemical space for drug-like molecules. Such interactions may account for side-effects or undesirable properties associated with otherwise well-validated GPCR targets. Understanding and/or intervening in these interactions may allow scientists to progress those targets that may have been deemed unsuitable for therapeutic intervention. The present study reviews the opportunities for utilizing receptor interacting proteins as potential drug targets and the issues associated with them.

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