Molecular Modeling of Quinoline-Based Compounds as Potential Dual Inhibitors of Reverse Transcriptase and Integrase of HIV

Alberto Cabrera,José L Medina-Franco,Daniel Chávez,Leonor Huerta Hernández

doi:10.4236/cmb.2018.83007

Abstract

As follow-up of our past publication [1], we propose that quinolones (as part of the pyridinone family) are capable to increase the number of interactions with HIV reverse transcriptase (RT) or integrase (IN) by adding a halogen in position C-8 of aromatic portion of the quinolones. This addition could help with the activity of dual inhibitors of RT and IN. In this work, we add a chlorine atom with the rationale to identify in the docking simulations a halogen interaction with the oxygen in the near aminoacids in the binding pockets of RT and IN enzymes. Our docking studies started with RT and 320 structures. Later, we took 73 structures with good results in docking with RT. The structures that we choose contain ester or acids groups in C-3 due the structural similarity with groups in charge to interact with the Mg++ ions in Elvitegravir. In conclusion, we obtained 14 structures that could occupy the allosteric pocket of RT and could inhibit the catalytic activity of IN, for this reason could be dual inhibitors. A major perspective of this work is the synthesis and testing of the potential dual inhibitors designed.

Highlights

In our research group we were working with pyridinone derivates as antiretroviral against HIV-1 [1] [2]
As follow-up of our past publication [1], we propose that quinolones are capable to increase the number of interactions with HIV reverse transcriptase (RT) or integrase (IN) by adding a halogen in position C-8 of aromatic portion of the quinolones
The quinolone ring has an aromatic portion facilitating the making of analogues or adding substituents that could contribute to the activity of the compounds

Summary

Introduction

In our research group we were working with pyridinone derivates as antiretroviral against HIV-1 [1] [2]. The substituents in the pyridinone derivates could interact with Mg++ ions located in a small space between DNA and IN in the nucleus of the cell This is to avoid that the enzyme IN blocks the action of DNA as proposed by Wang et al [6]. The quinolone ring has an aromatic portion facilitating the making of analogues or adding substituents that could contribute to the activity of the compounds. Based on this rationale, here we designed compounds that have in common a chlorine substituent in C-8 of the quinolones and have the basic structure of the pharmacophore published by Freeman et al [7]. It’s possible that the chlorine in C-8 position could contribute in the activity of the molecule of quinolone as RT or IN inhibitor due a halogen bond with other aminoacids [9]

Objectives

Methods

Results

Conclusion