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

Abstract Background 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. To understand and elucidate structure activity relationship and mechanism of inhibition of telomer...

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Autores principales:	R. D. Jawarkar, R. L. Bakal, P. N. Khatale, Israa Lewaa, Chetan M. Jain, Jagdish V. Manwar, Minal S. Jaiswal
Formato:	article
Lenguaje:	EN
Publicado:	SpringerOpen 2021
Materias:	QSAR TERT Telomeric G-quadruplex DNA Molecular docking Therapeutics. Pharmacology RM1-950 Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/aea501f2e5bc41f4ae3358eb9f160c10
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spelling	oai:doaj.org-article:aea501f2e5bc41f4ae3358eb9f160c102021-11-28T12:30:10ZQSAR, 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 DNA10.1186/s43094-021-00380-72314-7253https://doaj.org/article/aea501f2e5bc41f4ae3358eb9f160c102021-11-01T00:00:00Zhttps://doi.org/10.1186/s43094-021-00380-7https://doaj.org/toc/2314-7253Abstract Background 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. 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. Results Two robust QSAR model were obtained which consist of full set QSAR model (R 2: 0.8174, CCCtr: 0.8995, Q 2 loo: 0.7881, Q 2 LMO: 0.7814) and divided set QSAR model (R 2: 0.8217, CCCtr: 0.9021, Q 2 loo: 0.7886, Q 2 LMO: 0.7783, Q 2-F1: 0.7078, Q 2-F2: 0.6865, Q 2-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. Conclusion The 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 abstractR. D. JawarkarR. L. BakalP. N. KhataleIsraa LewaaChetan M. JainJagdish V. ManwarMinal S. JaiswalSpringerOpenarticleQSARTERTTelomericG-quadruplex DNAMolecular dockingTherapeutics. PharmacologyRM1-950Pharmacy and materia medicaRS1-441ENFuture Journal of Pharmaceutical Sciences, Vol 7, Iss 1, Pp 1-24 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	QSAR TERT Telomeric G-quadruplex DNA Molecular docking Therapeutics. Pharmacology RM1-950 Pharmacy and materia medica RS1-441
spellingShingle	QSAR TERT Telomeric G-quadruplex DNA Molecular docking Therapeutics. Pharmacology RM1-950 Pharmacy and materia medica RS1-441 R. D. Jawarkar R. L. Bakal P. N. Khatale Israa Lewaa Chetan M. Jain Jagdish V. Manwar Minal S. Jaiswal 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
description	Abstract Background 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. 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. Results Two robust QSAR model were obtained which consist of full set QSAR model (R 2: 0.8174, CCCtr: 0.8995, Q 2 loo: 0.7881, Q 2 LMO: 0.7814) and divided set QSAR model (R 2: 0.8217, CCCtr: 0.9021, Q 2 loo: 0.7886, Q 2 LMO: 0.7783, Q 2-F1: 0.7078, Q 2-F2: 0.6865, Q 2-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. Conclusion The 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
format	article
author	R. D. Jawarkar R. L. Bakal P. N. Khatale Israa Lewaa Chetan M. Jain Jagdish V. Manwar Minal S. Jaiswal
author_facet	R. D. Jawarkar R. L. Bakal P. N. Khatale Israa Lewaa Chetan M. Jain Jagdish V. Manwar Minal S. Jaiswal
author_sort	R. D. Jawarkar
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	SpringerOpen
publishDate	2021
url	https://doaj.org/article/aea501f2e5bc41f4ae3358eb9f160c10
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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

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