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Effect of Biomolecular Conformation on Docking Simulation: A Case Study on a Potent HIV-1 Protease Inhibitor.

Razzaghi-Asl N, Sepehri S, Ebadi A, Miri R, Shahabipour S - Iran J Pharm Res (2015)

Bottom Line: In the present contribution, the effect of HIV-1 PR flexibility (within multiple crystallographic structures of HIV-1 PR) on binding to the Amprenavir was elucidated via an ensemble docking approach.The outcomes of this study demonstrated that conformation of receptor may significantly affect the accuracy of docking/binding results in structure-based rational design of anti HIV-1 PR agents.Furthermore; some strategies to re-score the docking results in HIV-1 PR targeted docking studies were proposed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran. ; Drug and Advanced Sciences Research Center, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.

ABSTRACT
Human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) is a disease pertained to the human immune system. Given its crucial role in viral replication, HIV-1 protease (HIV-1 PR) is a prime therapeutic target in AIDS therapy. In this regard, the dynamic aspects of ligand-enzyme interactions may indicate an important role of conformational variability in HIV-1 PR inhibitor/drug design. In the present contribution, the effect of HIV-1 PR flexibility (within multiple crystallographic structures of HIV-1 PR) on binding to the Amprenavir was elucidated via an ensemble docking approach. Molecular docking studies were performed via advanced AutoDock4.2 software. Ensemble docking of Amprenavir into the active site of various conformations of HIV-1 PR predicted different interaction modes/energies. Analysis of binding factors in terms of docking false negatives/positives revealed a determinant role of enzyme conformational variation in prediction of optimum induced fit (PDB ID: 1HPV). The outcomes of this study demonstrated that conformation of receptor may significantly affect the accuracy of docking/binding results in structure-based rational design of anti HIV-1 PR agents. Furthermore; some strategies to re-score the docking results in HIV-1 PR targeted docking studies were proposed.

No MeSH data available.


Related in: MedlinePlus

Chemical structure of Amprenavir
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Figure 1: Chemical structure of Amprenavir

Mentions: In continuation to our interest in structure based modeling of bioactive molecules (15, 16) and to further elucidate the important role of target conformation in molecular docking results, we decided to explore the significance of HIV-1 PR flexibility through ensemble docking of Amprenavir into the multiple crystallographic structures of HIV-1 proteases (17, 18). Amprenavir (Figure 1) is a potent and selective HIV-1 PR inhibitor with sub-nanomolar HIV-1 PR inhibition activity (ki=0.6 nM) (19, 20) and hence was selected as a model in our studies.


Effect of Biomolecular Conformation on Docking Simulation: A Case Study on a Potent HIV-1 Protease Inhibitor.

Razzaghi-Asl N, Sepehri S, Ebadi A, Miri R, Shahabipour S - Iran J Pharm Res (2015)

Chemical structure of Amprenavir
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4518107&req=5

Figure 1: Chemical structure of Amprenavir
Mentions: In continuation to our interest in structure based modeling of bioactive molecules (15, 16) and to further elucidate the important role of target conformation in molecular docking results, we decided to explore the significance of HIV-1 PR flexibility through ensemble docking of Amprenavir into the multiple crystallographic structures of HIV-1 proteases (17, 18). Amprenavir (Figure 1) is a potent and selective HIV-1 PR inhibitor with sub-nanomolar HIV-1 PR inhibition activity (ki=0.6 nM) (19, 20) and hence was selected as a model in our studies.

Bottom Line: In the present contribution, the effect of HIV-1 PR flexibility (within multiple crystallographic structures of HIV-1 PR) on binding to the Amprenavir was elucidated via an ensemble docking approach.The outcomes of this study demonstrated that conformation of receptor may significantly affect the accuracy of docking/binding results in structure-based rational design of anti HIV-1 PR agents.Furthermore; some strategies to re-score the docking results in HIV-1 PR targeted docking studies were proposed.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran. ; Drug and Advanced Sciences Research Center, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.

ABSTRACT
Human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) is a disease pertained to the human immune system. Given its crucial role in viral replication, HIV-1 protease (HIV-1 PR) is a prime therapeutic target in AIDS therapy. In this regard, the dynamic aspects of ligand-enzyme interactions may indicate an important role of conformational variability in HIV-1 PR inhibitor/drug design. In the present contribution, the effect of HIV-1 PR flexibility (within multiple crystallographic structures of HIV-1 PR) on binding to the Amprenavir was elucidated via an ensemble docking approach. Molecular docking studies were performed via advanced AutoDock4.2 software. Ensemble docking of Amprenavir into the active site of various conformations of HIV-1 PR predicted different interaction modes/energies. Analysis of binding factors in terms of docking false negatives/positives revealed a determinant role of enzyme conformational variation in prediction of optimum induced fit (PDB ID: 1HPV). The outcomes of this study demonstrated that conformation of receptor may significantly affect the accuracy of docking/binding results in structure-based rational design of anti HIV-1 PR agents. Furthermore; some strategies to re-score the docking results in HIV-1 PR targeted docking studies were proposed.

No MeSH data available.


Related in: MedlinePlus