QSAR, pharmacophore modeling and molecular docking studies to identify structural alerts for some nitrogen heterocycles as dual inhibitor of telomerase reverse transcriptase and human telomeric G-quadruplex DNA

R D Jawarkar,Chetan M Jain,Israa Lewaa,P N Khatale,Minal S Jaiswal,Jagdish V Manwar,R L Bakal

doi:10.1186/s43094-021-00380-7

Abstract

BackgroundTelomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA are amongst the favorable target for researchers to discover novel and more effective anticancer agents. To understand and elucidate structure activity relationship and mechanism of inhibition of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA, a QSAR modeling and molecular docking were conducted.ResultsTwo robust QSAR model were obtained which consist of full set QSAR model (R2: 0.8174, CCCtr: 0.8995, Q2loo: 0.7881, Q2LMO: 0.7814) and divided set QSAR model (R2: 0.8217, CCCtr: 0.9021, Q2loo: 0.7886, Q2LMO: 0.7783, Q2-F1: 0.7078, Q2-F2: 0.6865, Q2-F3: 0.7346) for envisaging the inhibitory activity of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA. The analysis reveals that carbon atom exactly at 3 bonds from aromatic carbon atom, nitrogen atom exactly at six bonds from planer nitrogen atom, aromatic carbon atom within 2 A0 from the center of mass of molecule and occurrence of element hydrogen within 2 A0 from donar atom are the key pharmacophoric features important for dual inhibition of TERT and human telomeric G-quadruplex DNA. To validate this analysis, pharmacophore modeling and the molecular docking is performed. Molecular docking analysis support QSAR analysis and revealed that, dual inhibition of TERT and human telomeric DNA is mainly contributed from hydrophobic and hydrogen bonding interactions.ConclusionThe findings of molecular docking, pharmacophore modelling, and QSAR are all consistent and in strong agreement. The validated QSAR analyses can detect structural alerts, pharmacophore modelling can classify a molecule's consensus pharmacophore involving hydrophobic and acceptor regions, whereas docking analysis can reveal the mechanism of dual inhibition of telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA. The combination of QSAR, pharmacophore modeling and molecular docking may be useful for the future drug design of dual inhibitors to combat the devastating issue of resistance.Graphical abstract

Highlights

Telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA are amongst the favorable target for researchers to discover novel and more effective anticancer agents
R2: 0.8174, R2adj: 0.8054, R2–R2adj: 0.0120, LOF: 0.1499, Kxx: 0.2604, Delta K: 0.1186, RMSEtr: 0.3400, MAEtr: 0.2510, R SStr: 9.4780, CCCtr: 0.8995, s: 0.3531, F: 68.0476, Q2loo: 0.7881, R2–Q2loo: 0.0293, R MSEcv: 0.3663, MAEcv: 0.2702, PRESScv: 11.0009, CCCcv: 0.8831, Q2LMO: 0.7814, R2Yscr: 0.0597, Q2Yscr: − 0.0987, RMSE AV Yscr: 0.7714. (Depiction of Quantitative structure–activity relationship (QSAR) results along with their experimental and predicted E C50 values for full set model is given in Additional file 1: Table S4)
In the present QSAR analysis, compound 82 was detected as X outlier while compound 8, 13 were depicted as high leverage influential

Summary

Introduction

Telomerase reverse transcriptase (TERT) and human telomeric G-quadruplex DNA are amongst the favorable target for researchers to discover novel and more effective anticancer agents. The analysis reveals that carbon atom exactly at 3 bonds from aromatic carbon atom, nitrogen atom exactly at six bonds from planer nitrogen atom, aromatic carbon atom within 2 A 0 from the center of mass of molecule and occurrence of element hydrogen within 2 A0 from donar atom are the key pharmacophoric features important for dual inhibition of TERT and human telomeric G-quadruplex DNA To validate this analysis, pharmacophore modeling and the molecular docking is performed. Transcriptase has emerged as a possible drug target in cancer therapeutics because of following whys and wherefores [1]: Every human being has telomerase, which is active in the early stages of life to preserve telomere duration This will maintain the chromosomal integrity of recurrently dividing cells, which is supposed to be inactive in most somatic cells and is maintained during adulthood [1]. Many hTERT inhibitors were reported [2, 7], and some of them, comprising BIBR1532 [8–10] showed promising anticancer effects [11–13]

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