Abstract
Objective: The reason for the failure of most of the anti-HIV drugs are their poor pharmacokinetics, the poor risk to benefit ratio and the drug resistance. With the objective of developing newer pyrazole scaffolds for effective treatment of HIV, binding mode analysis of designing ligands with the HIV-1RT protein and prediction of key ADME and toxicity parameters of the compounds was in an area of interest.Methods: In this study, molecular docking studies and ADME-T studies were carried out in designing of some novel pyrazole analogs. The protein (PDB ID: 1RT2) was prepared using the Protein Preparation Wizard (Schrodinger Glide 5.0). ADME parameters calculated by QikProp 3.0v and toxicity of designed analogs checked by using two different online software’s namely Lazar and protox.Results: Most of the designed pyrazole analogs have good oral absorption as well as good binding affinity towards HIV-1 reverse transcriptase.Conclusion: Finally total 5 analogs (SGS-2, 3, 12, 13 and 14) from the 14 designed leads were found to be best on the basis of molecular docking and ADME-T studies.
Highlights
The replication of the retrovirus takes place in two steps
The nonnucleoside reverse transcriptase inhibitors are a category of drugs that have been developed and approved by USFDA for the treatment of human immunodeficiency virus (HIV)-1 infection [2, 3]
There are a few successful drugs developed the booming prevalence of resistance to these drug candidates and a pulse of their adverse effects made it essential to develop antiviral agents which are active against mutant HIV strains
Summary
The transcription of a single-stranded (+) RNA genome into a doublestranded DNA and in the second step, an integration of these into the host genome [1, 2]. Resistance exerted by the wild-type HIV-1 strains were attributed to this fact In addition to their high specificity to the binding pockets, high potency, and low cytotoxicity made the second-generation nonnucleoside reverse transcriptase inhibitors the drug of choice to treat the HIV infection. The structural flexibility of second-generation nonnucleoside reverse transcriptase inhibitors, etravirine, rilpivirine is to bind to the mutated nonnucleoside binding pocket thereby being more effective compared to older drugs [5]. The poor pharmacokinetics, unsatisfactory side effects and the rapid appearance of drug resistance of the these clinically approved antiHIV drugs compelled the medicinal chemist to develop novel nonnucleoside reverse transcriptase inhibitors or modify the existing nonnucleoside reverse transcriptase inhibitors [6,7,8]
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