In-silico design and study of novel piperazinyl β-carbolines as inhibitor of HIV-1 reverse transcriptase

Abstract

Despite of all the extensive research work done on recently developed diaryl pyrimidine analogues, thiazolidinedione analogues and indolyl aryl sulfones as HIV-1 reverse transcriptase (RT) inhibitors, there still continues the never-ending problem of resistance. In the present study, we have designed novel β-carboline analogues as inhibitor of HIV-1 RT. Molecular docking studies were performed using Autodock v4.2 against both wild and mutant strains of HIV-1 RT. Among the designed analogues, compound 9H3NH4CN, 9H6CNP and 9H4CN showed significant binding free energy against wild strain (−10.99, −12.06, −11.33 kcal/mol) and against mutant strain (−15.27, −13.9, −15.81 kcal/mol) of HIV-1 RT, respectively, as that of standard drugs efavirenz, rilpivirine against wild strain (−12.02, −8.55 kcal/mol) and against mutant strain (−10.81, −12.1 kcal/mol) of HIV-1 RT, respectively. The predicted inhibitory constant values (K i) of these compounds are against wild strain (8.8, 1.37, 4.92 nM) and against mutant strain (6.4, 64.43, 2.56 pM), respectively, as that of standard drugs efavirenz, rilpivirine against wild strain (1.6, 538.7 nM) and against mutant strain (11.8, 1.36 nM) of HIV-1 RT, respectively. In addition to this, molecular descriptors such as Lipinski drug likeness and ADMET properties were calculated using online servers like Molinspiration and admetSAR. These compounds can be further developed as next generation non-nucleoside reverse transcriptase inhibitors with promising anti HIV-1 activity with better pharmacokinetic profile.