Molecular modeling study on the allosteric inhibition mechanism of HIV-1 integrase by LEDGF/p75 binding site inhibitors.

Weiwei Xue,Xiaojun Yao,Huanxiang Liu

doi:10.1371/journal.pone.0090799

Weiwei Xue, Xiaojun Yao + Show 1 more

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https://doi.org/10.1371/journal.pone.0090799

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Abstract

HIV-1 integrase (IN) is essential for the integration of viral DNA into the host genome and an attractive therapeutic target for developing antiretroviral inhibitors. LEDGINs are a class of allosteric inhibitors targeting LEDGF/p75 binding site of HIV-1 IN. Yet, the detailed binding mode and allosteric inhibition mechanism of LEDGINs to HIV-1 IN is only partially understood, which hinders the structure-based design of more potent anti-HIV agents. A molecular modeling study combining molecular docking, molecular dynamics simulation, and binding free energy calculation were performed to investigate the interaction details of HIV-1 IN catalytic core domain (CCD) with two recently discovered LEDGINs BI-1001 and CX14442, as well as the LEDGF/p75 protein. Simulation results demonstrated the hydrophobic domain of BI-1001 and CX14442 engages one subunit of HIV-1 IN CCD dimer through hydrophobic interactions, and the hydrophilic group forms hydrogen bonds with HIV-1 IN CCD residues from other subunit. CX14442 has a larger tert-butyl group than the methyl of BI-1001, and forms better interactions with the highly hydrophobic binding pocket of HIV-1 IN CCD dimer interface, which can explain the stronger affinity of CX14442 than BI-1001. Analysis of the binding mode of LEDGF/p75 with HIV-1 IN CCD reveals that the LEDGF/p75 integrase binding domain residues Ile365, Asp366, Phe406 and Val408 have significant contributions to the binding of the LEDGF/p75 to HIV1-IN. Remarkably, we found that binding of BI-1001 and CX14442 to HIV-1 IN CCD induced the structural rearrangements of the 140 s loop and oration displacements of the side chains of the three conserved catalytic residues Asp64, Asp116, and Glu152 located at the active site. These results we obtained will be valuable not only for understanding the allosteric inhibition mechanism of LEDGINs but also for the rational design of allosteric inhibitors of HIV-1 IN targeting LEDGF/p75 binding site.

Highlights

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS) [1,2]
In this work, using an combined computational approach, we explored the structural and energetic properties of the recently discovered two LEDGF/p75 binding site of integrase (LEDGINs) BI-1001 and CX14442, as well as the Lens Epithelium Derived Growth Factor (LEDGF)/p75 bound to the HIV-1 IN catalytic core domain (CCD) dimer interface
On the basis of our modified co-crystal structure 4DMN, the interaction mode between the HIV-1 IN CCD allosteric site and the CX14442 was obtained by using molecular docking approach

Summary

Introduction

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS) [1,2]. IN acts on the viral DNA attachment sites at the ends of the linear reverse transcript to effectively insert the reverse transcript into a host cell chromosome in a two-step reaction: 39-processing and strand transfer [3,4,5]. Following 39-processing, the IN protein removes two nucleotides from each 39 end of the viral DNA, leaving recessed CA hydroxyl group at the 39 end. After this cleavage, the IN protein remains bound to the viral DNA and joins the previously 39 end to the 59 end of strands of host cell chromosomal DNA. Many integrase strand transfer inhibitors (INSTIs) with different chemical scaffolds targeting the strand transfer reaction of HIV-

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