Comparative Docking Study of Anibamine as the First Natural Product CCR5 Antagonist in CCR5 Homology Models

Guo, Li; Haney, Kendra M.; Kellogg, Glen E.; Zhang, Yan

doi:10.1021/ci800356a

Cited by 34 publications

(29 citation statements)

References 150 publications

(100 reference statements)

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“…In such cases, molecular modeling studies that build and refine homology models of the receptor and dock certain ligands into these models are the most accessible approaches to studying the 3D conformation of the receptor and binding mode of the ligands. Similar homology modeling approaches have been successfully applied to many different GPCRs [13–16]. These studies provide valuable information regarding binding modes of ligands and identifying amino acid residues that are crucial for ligand recognition.…”

Section: Introductionmentioning

confidence: 99%

A homology modeling study toward the understanding of three-dimensional structure and putative pharmacological profile of the G-protein coupled receptor GPR55

Elbegdorj

Westkaemper

Zhang

2013

Journal of Molecular Graphics and Modelling

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The orphan G-protein coupled receptor GPR55 was shown to bind to certain cannabinoid compounds which led to its initial classification as the third type of cannabinoid receptor. Later studies showed that lysophosphatidylinositol (LPI) also activated GPR55, in particular 2-arachidonoyl-LPI was proposed to be its endogenous ligand. However, the results of pharmacological studies regarding GPR55 have been quite inconsistent. Despite its contradictory pharmacological profile, GPR55 has been implicated in various disease states including inflammatory and neuropathic pain, metabolic bone diseases, and cancer. Herein, we report the ligand binding properties of GPR55 by applying homology modeling and automated docking algorithms in order to understand its pharmacological profile. The 3D homology model of GPR55 was built based on the Adenosine A2A receptor crystal structure. Docking studies of several types of reported ligands were carried out afterwards. The results indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and the amino acid residue Lys80 seemed to be the anchor residue for receptor recognition. In addition, its putative agonist and antagonist appeared to recognize different domains of the receptor corresponding to their reported pharmacological activities.

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Section: Introductionmentioning

confidence: 99%

A homology modeling study toward the understanding of three-dimensional structure and putative pharmacological profile of the G-protein coupled receptor GPR55

Elbegdorj

Westkaemper

Zhang

2013

Journal of Molecular Graphics and Modelling

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“…The mutations of the above residues are found to dramatically reduce the inhibitory activities of the antagonist. 61 A recent homology modeling study 70 based on the crystal structures of bovine rhodopsin and the human β2-adrenergic receptor observed a similar binding mode between Vic and CCR5.…”

Section: Resultsmentioning

confidence: 98%

Theoretical Studies on the Interactions and Interferences of HIV-1 Glycoprotein gp120 and Its Coreceptor CCR5

2011

J. Chem. Inf. Model.

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The interaction between the HIV gp120 protein and coreceptor CCR5 or CXCR4 of the host cell is critical in mediating the HIV entry process. A model for the CCR5-gp120 complex has been developed. In the model, the N-terminus of CCR5 binds to three discontinuous domains of gp120, including the fourth conserved (C4) region, β19/β20 connecting loop, and V3 loop. The second extra-cellular loop (ECL2) of CCR5 also interacts with the crown part of the gp120 V3 loop. The bindings of the three CCR5 antagonists, maraviroc, aplaviroc, and vicriviroc, to the trans-membrane domain of CCR5 have been modeled. The bindings are found to affect the conformation of the ECL2 domain, which in turn drives the N-terminus of CCR5 to an altered state. Aplaviroc is more hydrophilic than maraviroc and vicriviroc, and its binding is more interfered by solvent, resulting in a quite different effect to the structure of CCR5 compared with those of the other two molecules. The above results are in accord with experimental observations and provide a structural basis for further design of CCR5 antagonists.

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“…Homology modeling was the main computational method for CCR5 antagonist development before 2013. Several studies were performed on the human CCR5 structure construction via homology modeling by using the X-ray structure of the bovine rhodopsin receptor (61)(62)(63)(64). Additionally, a homology model of human CCR5 was developed based on the reported CXCR4 structure as a template (65).…”

Section: Ccr5mentioning

confidence: 99%

Anti-HIV Drug Development Through Computational Methods

Zhang

Yuan

2014

AAPS J

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Abstract. Although highly active antiretroviral therapy (HAART) is effective in controlling the progression of AIDS, the emergence of drug-resistant strains increases the difficulty of successful treatment of patients with HIV infection. Increasing numbers of patients are facing the dilemma that comes with the running out of drug combinations for HAART. Computational methods play a key role in anti-HIV drug development. A substantial number of studies have been performed in anti-HIV drug development using various computational methods, such as virtual screening, QSAR, molecular docking, and homology modeling, etc. In this review, we summarize recent advances in the application of computational methods to anti-HIV drug development for five key targets as follows: reverse transcriptase, protease, integrase, CCR5, and CXCR4. We hope that this review will stimulate researchers from multiple disciplines to consider computational methods in the anti-HIV drug development process.

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Comparative Docking Study of Anibamine as the First Natural Product CCR5 Antagonist in CCR5 Homology Models

Cited by 34 publications

References 150 publications

A homology modeling study toward the understanding of three-dimensional structure and putative pharmacological profile of the G-protein coupled receptor GPR55

A homology modeling study toward the understanding of three-dimensional structure and putative pharmacological profile of the G-protein coupled receptor GPR55

Theoretical Studies on the Interactions and Interferences of HIV-1 Glycoprotein gp120 and Its Coreceptor CCR5

Anti-HIV Drug Development Through Computational Methods

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