Hit identification and drug repositioning of potential non-nucleoside reverse transcriptase inhibitors by structure-based approach using computational tools (part II)

Pretisha Flora Cutinho, Ravi C. Shankar, Avinash Anand, Jaydeep Roy, Chetan H. Mehta, Usha Y. Nayak, Manikanta Murahari

Research output: Contribution to journalArticle

Abstract

AIDS is a global infection involving several complications and its increasing prevalence every year has prioritized our study. Therapy associated with HIV has led to emergence of multidrug resistance and toxicity. Thus, the development of a potent, affordable and safe anti-HIV drug is a global concern. Among the different targets developed, inhibition of non-nucleoside reverse transcriptase (NNRT) is found to be effective and promising. Etravirine, efavirenz, nevirapine, rilpivirine and delavirdine are the marketed NNRTIs available. This study is focused on computational prediction of hit molecules as well as repurposing of various FDA-approved drugs as potential NNRTIs. A synthetic database from ZINCpharmer, publicly available natural databases of coumarins, chromones and chalcones, and two databases of FDA-approved drugs for repurposing were screened to check for the possibility of these compounds to possess anti-HIV activity. Study utilizes a structure-based approach with the generated pharmacophore of target protein (PDB ID: 3MEC), screening of selected datasets is carried out using the Phase tool of Schrodinger. The top filtered compounds with good fitness score were proceeded to molecular docking studies to study their binding affinity to the target. Energy-based calculations using Prime MM-GBSA of Schrodinger was performed to determine free binding energy of the complexes. Prediction of pharmacokinetic parameters of top compounds is further carried out and reported. All the results obtained from different databases are compiled, interpreted and five molecules were subjected to molecular dynamic studies to further confirm the prediction and identified hit molecules for in vitro screening as potential NNRTIs. Communicated by Ramaswamy H. Sarma.

Original languageEnglish
JournalJournal of Biomolecular Structure and Dynamics
DOIs
Publication statusAccepted/In press - 01-01-2019

Fingerprint

Drug Repositioning
Reverse Transcriptase Inhibitors
Databases
Rilpivirine
efavirenz
etravirine
Delavirdine
Chromones
HIV
Chalcones
Nevirapine
Anti-HIV Agents
Coumarins
RNA-Directed DNA Polymerase
Multiple Drug Resistance
Molecular Dynamics Simulation
Acquired Immunodeficiency Syndrome
Pharmacokinetics
Infection
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

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title = "Hit identification and drug repositioning of potential non-nucleoside reverse transcriptase inhibitors by structure-based approach using computational tools (part II)",
abstract = "AIDS is a global infection involving several complications and its increasing prevalence every year has prioritized our study. Therapy associated with HIV has led to emergence of multidrug resistance and toxicity. Thus, the development of a potent, affordable and safe anti-HIV drug is a global concern. Among the different targets developed, inhibition of non-nucleoside reverse transcriptase (NNRT) is found to be effective and promising. Etravirine, efavirenz, nevirapine, rilpivirine and delavirdine are the marketed NNRTIs available. This study is focused on computational prediction of hit molecules as well as repurposing of various FDA-approved drugs as potential NNRTIs. A synthetic database from ZINCpharmer, publicly available natural databases of coumarins, chromones and chalcones, and two databases of FDA-approved drugs for repurposing were screened to check for the possibility of these compounds to possess anti-HIV activity. Study utilizes a structure-based approach with the generated pharmacophore of target protein (PDB ID: 3MEC), screening of selected datasets is carried out using the Phase tool of Schrodinger. The top filtered compounds with good fitness score were proceeded to molecular docking studies to study their binding affinity to the target. Energy-based calculations using Prime MM-GBSA of Schrodinger was performed to determine free binding energy of the complexes. Prediction of pharmacokinetic parameters of top compounds is further carried out and reported. All the results obtained from different databases are compiled, interpreted and five molecules were subjected to molecular dynamic studies to further confirm the prediction and identified hit molecules for in vitro screening as potential NNRTIs. Communicated by Ramaswamy H. Sarma.",
author = "Cutinho, {Pretisha Flora} and Shankar, {Ravi C.} and Avinash Anand and Jaydeep Roy and Mehta, {Chetan H.} and Nayak, {Usha Y.} and Manikanta Murahari",
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Hit identification and drug repositioning of potential non-nucleoside reverse transcriptase inhibitors by structure-based approach using computational tools (part II). / Cutinho, Pretisha Flora; Shankar, Ravi C.; Anand, Avinash; Roy, Jaydeep; Mehta, Chetan H.; Nayak, Usha Y.; Murahari, Manikanta.

In: Journal of Biomolecular Structure and Dynamics, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Cutinho, Pretisha Flora

AU - Shankar, Ravi C.

AU - Anand, Avinash

AU - Roy, Jaydeep

AU - Mehta, Chetan H.

AU - Nayak, Usha Y.

AU - Murahari, Manikanta

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N2 - AIDS is a global infection involving several complications and its increasing prevalence every year has prioritized our study. Therapy associated with HIV has led to emergence of multidrug resistance and toxicity. Thus, the development of a potent, affordable and safe anti-HIV drug is a global concern. Among the different targets developed, inhibition of non-nucleoside reverse transcriptase (NNRT) is found to be effective and promising. Etravirine, efavirenz, nevirapine, rilpivirine and delavirdine are the marketed NNRTIs available. This study is focused on computational prediction of hit molecules as well as repurposing of various FDA-approved drugs as potential NNRTIs. A synthetic database from ZINCpharmer, publicly available natural databases of coumarins, chromones and chalcones, and two databases of FDA-approved drugs for repurposing were screened to check for the possibility of these compounds to possess anti-HIV activity. Study utilizes a structure-based approach with the generated pharmacophore of target protein (PDB ID: 3MEC), screening of selected datasets is carried out using the Phase tool of Schrodinger. The top filtered compounds with good fitness score were proceeded to molecular docking studies to study their binding affinity to the target. Energy-based calculations using Prime MM-GBSA of Schrodinger was performed to determine free binding energy of the complexes. Prediction of pharmacokinetic parameters of top compounds is further carried out and reported. All the results obtained from different databases are compiled, interpreted and five molecules were subjected to molecular dynamic studies to further confirm the prediction and identified hit molecules for in vitro screening as potential NNRTIs. Communicated by Ramaswamy H. Sarma.

AB - AIDS is a global infection involving several complications and its increasing prevalence every year has prioritized our study. Therapy associated with HIV has led to emergence of multidrug resistance and toxicity. Thus, the development of a potent, affordable and safe anti-HIV drug is a global concern. Among the different targets developed, inhibition of non-nucleoside reverse transcriptase (NNRT) is found to be effective and promising. Etravirine, efavirenz, nevirapine, rilpivirine and delavirdine are the marketed NNRTIs available. This study is focused on computational prediction of hit molecules as well as repurposing of various FDA-approved drugs as potential NNRTIs. A synthetic database from ZINCpharmer, publicly available natural databases of coumarins, chromones and chalcones, and two databases of FDA-approved drugs for repurposing were screened to check for the possibility of these compounds to possess anti-HIV activity. Study utilizes a structure-based approach with the generated pharmacophore of target protein (PDB ID: 3MEC), screening of selected datasets is carried out using the Phase tool of Schrodinger. The top filtered compounds with good fitness score were proceeded to molecular docking studies to study their binding affinity to the target. Energy-based calculations using Prime MM-GBSA of Schrodinger was performed to determine free binding energy of the complexes. Prediction of pharmacokinetic parameters of top compounds is further carried out and reported. All the results obtained from different databases are compiled, interpreted and five molecules were subjected to molecular dynamic studies to further confirm the prediction and identified hit molecules for in vitro screening as potential NNRTIs. Communicated by Ramaswamy H. Sarma.

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