Expanding GPCR homology model binding sites via a balloon potential: A molecular dynamics refinement approach

Kimura, Seiichiro; Tebben, Andrew J.; Langley, David R.

doi:10.1002/prot.21906

Cited by 38 publications

(41 citation statements)

References 45 publications

(64 reference statements)

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“…Previously homology models of CCR2 were developed using the traditionally used bovine rhodopsin and the recently reported β 2 -adrenergic receptors as templates. 21,[54][55][56] In this study we used the recently reported CXCR4 (PDB code: 3ODU) as a template and modeling was done because of the non-availability of crystal structure. A molecular docking study was then performed with 16b of 4AAC against the proposed binding site.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

Kothandan¹,

Gadhe²,

Cho³

2013

Bulletin of the Korean Chemical Society

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Chemokine receptor (CCR2) is a G protein-coupled receptor that contains seven transmembrane helices. Recent pharmaceutical research has focused on the antagonism of CCR2 and candidate drugs are currently undergoing clinical studies for the treatment of diseases like arthritis, multiple sclerosis, and type 2 diabetes. In this study, we analyzed the time dependent behavior of CCR2 docked with a potent 4-azetidinyl-1-arylcyclohexane (4AAC) derivative using molecular dynamics simulations (MDS) for 20 nanoseconds (ns). Homology modeling of CCR2 was performed and the 4AAC derivative was docked into this binding site. The docked model of selected conformations was then utilized to study the dynamic behavior of the 4AAC enzyme complexes inside lipid membrane. MDS of CCR2-16b of 4AAC complexes allowed us to refine the system since binding of an inhibitor to a receptor is a dynamic process and identify stable structures and better binding modes. Structure activity relationships (SAR) for 4AAC derivatives were investigated and reasons for the activities were determined. Probable binding pose for some CCR2 antagonists were determined from the perspectives of binding site. Initial modeling showed that Tyr49, Trp98, Ser101, Glu291, and additional residues are crucial for 4AAC binding, but MDS analysis showed that Ser101 may not be vital. 4AAC moved away from Ser101 and the hydrogen bonding between 4AAC and Ser101 vanished. The results of this study provide useful information regarding the structure-based drug design of CCR2 antagonists and additionally suggest key residues for further study by mutagenesis.

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Section: Discussionmentioning

confidence: 99%

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

Kothandan¹,

Gadhe²,

Cho³

2013

Bulletin of the Korean Chemical Society

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“…A fourth study we discuss below focuses on a binding event in which the ligand travels along a predetermined pathway from the bulk solvent, towards a bound state within the receptor (Provasi et al 2009). We also comment on a novel method of altering the orthosteric binding pocket of receptor homology models, to permit successful docking of ligands of differing shape and size to that in the template structure (Kimura et al 2008). …”

Section: 2 Ligand Recognition In Gpcrsmentioning

confidence: 99%

Beyond Standard Molecular Dynamics: Investigating the Molecular Mechanisms of G Protein-Coupled Receptors with Enhanced Molecular Dynamics Methods

Johnston

Filizola

2013

Advances in Experimental Medicine and Biology

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The majority of biological processes mediated by G Protein-Coupled Receptors (GPCRs) take place on timescales that are not conveniently accessible to standard molecular dynamics (MD) approaches, notwithstanding the current availability of specialized parallel computer architectures, and efficient simulation algorithms. Enhanced MD-based methods have started to assume an important role in the study of the rugged energy landscape of GPCRs by providing mechanistic details of complex receptor processes such as ligand recognition, activation, and oligomerization. We provide here an overview of these methods in their most recent application to the field.

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“…Instead of inputting new ligand by structural alignment, docking-based global energy minimization via stochastic side chain movement, force fields or user-defined scoring function has become another refinement routine. This "ligand-centric" approach has been widely employed in identification of novel inhibitors against GPCR targets including MCH-R1, mGluR and CCR2 [29,34,[37][38][39]. Other applications include protein structural analysis and function prediction [40][41][42][43][44][45], understanding of protein-ligand interactions [46][47][48][49][50][51][52][53] and compound optimization [54][55][56].…”

Section: Homology Modelingmentioning

confidence: 99%

“…However, the imperfection of the constructed models may limit their applicability in structure-based design methods. Several methods have been reported to refine crude homology models or at least the side-chain conformations of the crucial binding [28][29][30][31][32][33][34]. Interested readers are encouraged to refer [10] for a comprehensive list of homology modeling programs and servers.…”

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confidence: 99%

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

Chen¹,

Morrow²,

Tran³

et al. 2012

curr drug metab

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As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. KeywordsStructure-based drug design; protein modeling; focused library design; pharmacophore; flexible docking; high-throughput virtual screening; de novo design; protein-protein interaction; polypharmacology Modern computational-aided drug design established a novel platform by which researchers perform in-depth in silico simulation prior to labor-extensive wet-lab validation [1]. It comprises of two major parts corresponding to the information of molecular source it utilizes: structure-based (or receptor-based) drug design and ligand-based drug design. Structure-based drug design, which relies on the knowledge of biological target structures, aims to discover small molecules/peptides leads with desired chemistry properties, and orchestrate the following experimental validation and lead optimization. Structure-based approach provides mechanism-based basis, where potential ligands are excavated using receptor-dependent parameters, while ligand-based approaches bypass the consideration of complex biomolecular "black box" in a living cell. This in silico method permeates all aspects of drug discovery today [2], and we expect it will draw more attentions with the unprecedented advances of computational power and modeling accuracy in this decade.* Corresponding author: Shuxing Zhang, Ph.D., The University of Texas M. D. Anderson Cancer Center, Department of Experimental Therapeutics, Unit 1950, 1901 East Rd., Houston, TX 77054, Telephone: (713)-745-2958 794-5577, shuzhang@mdanderson.org. Conflict of interestThe authors declare that they do not have competing interests. NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2013 November 07.Published in final edited form as:Curr Pharm Des. 2012 ; 18(9): 1217-1239. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn this review, we will overview the state-of-the-art structure-based drug discovery techniques ranging from receptor modeling to lead identification and optimization. In each topic, we will also highlight the fruitful successes as well as ch...

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Expanding GPCR homology model binding sites via a balloon potential: A molecular dynamics refinement approach

Cited by 38 publications

References 45 publications

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

Beyond Standard Molecular Dynamics: Investigating the Molecular Mechanisms of G Protein-Coupled Receptors with Enhanced Molecular Dynamics Methods

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

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