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Comb Chem High Throughput Screen. 2019 Dec 13. doi: 10.2174/1386207323666191213142223. [Epub ahead of print]

Three Major Phosphoacceptor Sites in HIV-1 Capsid Protein Enhances its Structural Stability and Resistance against Inhibitor: Explication through Molecular Dynamics Simulation, Molecular Docking and DFT Analysis.

Author information

1
Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270. Pakistan.
2
National Center of Artificial Intelligence, Punjab University College of Information Technology, University of the Punjab, Lahore. Pakistan.

Abstract

BACKGROUND:

Human immunodeficiency virus 1 (HIV-1) is a lentivirus which causes various HIV-associated infections. The HIV-1 core dissociation is essential for viral cDNA synthesis and phosphorylation of HIV-1 capsid protein (HIV-1 CA) plays an important role in it.

OBJECTIVE:

The aim of this study is to explicate the role of three phosphoserine sites i.e. Ser109, Ser149 and Ser178 in the structural stability of HIV-1 CA, and it's binding with GS-CA1, a novel potent inhibitor.

METHOD:

Eight complexes are analyzed and molecular dynamics (MD) simulations are performed to observe the stability of HIV-1 CA in the presence and absence of phosphorylation of serine residues at four different temperatures i.e. 300K, 325K, 340K and 350K, along with molecular docking and DFT analysis.

RESULTS:

The structures showed maximum stability in the presence of phosphorylated serine residue. However, GS-CA1 docked most strongly with the native structure of HIV-1 CA i.e. binding affinity was -8.5kcal/mol (Ki = 0.579 µM).

CONCLUSION:

These results suggest that the phosphorylation of these three serine residues weakens the binding of GS-CA1 with CA and casts derogatory effect on inhibition potential of this inhibitor, but it supports the stability of HIV-1 CA structure that can enhance regulation and replication of HIV-1 in host cells.

KEYWORDS:

DFT Analysis; GS-CA1; HIV-1 Capsid; Molecular Docking; Molecular Dynamics Simulation; Phosphorylation

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