Is the conformational flexibility of piperazine derivatives important to inhibit HIV-1 replication?

Tyrosine kinases are a wide family of targets with strong pharmacological relevance. These proteins undergo large-scale conformational motions able to inactivate them. By the end of one of these structural processes, a new cavity is opened allowing the access to a specific type of inhibitors, called type II. The kinase domain of fibroblast growth factor receptor 3 (FGFR3) falls into this family of kinases. We describe here, for the first time, its inactivation process through target molecular dynamics. The transient cavity, at the crossroad between the DFGout and Cα helix out inactivation is herein explored. Molecular docking calculations of known ligands demonstrated that type II inhibitors are able to interact with this metastable transient conformation of FGFR3 kinase. Besides, supplemental computations were conducted and clearly show that type II inhibitors drive the kinase inactivation process through specific stabilization with the DFG triad. This induced-fit effect of type II ligands toward FGFR3 might be extrapolated to other kinase systems and provides meaningful structural information for future drug developments.

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In silico study on indole derivatives as anti HIV-1 agents: a combined docking, molecular dynamics and 3D-QSAR study

Balupuri

Gadhe

Balasubramanian

et al. 2013

Arch. Pharm. Res.

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The HIV-1 envelope glycoprotein gp120 plays a vital role in the entry of virus into the host cells and is a potential antiviral drug target. Recently, indole derivatives have been reported to inhibit HIV-1 through binding to gp120, and this prevents gp120 and CD4 interaction to inhibit the infectivity of HIV-1. In this work, molecular docking, molecular dynamics (MD) and three-dimensional quantitative structure-activity relationship studies were carried out. Molecular docking studies of the most active and the least active compounds were performed to identify important residues in the binding pocket. We refined the docked poses by MD simulations which resulted in conformational changes. After equilibration, the structure of the ligand and receptor complex was stable. Therefore, we just took the last snapshot as the representative binding pose for this study. This pose for the most active inhibitor was used as a template for receptor-based alignment which was subsequently used for comparative molecular field analysis. Resultant 3D contour maps suggested smaller substituents are desirable at the 7-position of indole ring to avoid steric interactions with Ser375, Phe382 and Tyr384 residues in the active site. These results can be exploited to develop potential leads and for structure-based drug design of novel HIV-1 inhibitors.

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Is the conformational flexibility of piperazine derivatives important to inhibit HIV-1 replication?

Cited by 7 publications

References 37 publications

Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Nav) 1.3 channel modulators

Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Nav) 1.3 channel modulators

Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3)

In silico study on indole derivatives as anti HIV-1 agents: a combined docking, molecular dynamics and 3D-QSAR study

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