Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1

Abstract P21-activated kinases (PAKs) are serine/threonine protein kinase which have six different isoforms (PAK1–6). Of those, PAK1 is overexpressed in many cancers and considered to be a major chemotherapeutic target. Most of the developed PAK1 inhibitor drugs work as pan-PAK inhibitors and show u...

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Autores principales:	Md Shahinozzaman, Sinthyia Ahmed, Rashiduzzaman Emran, Shinkichi Tawata
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/97627965dec141f385e331f0e5a399ac
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spelling	oai:doaj.org-article:97627965dec141f385e331f0e5a399ac2021-12-02T15:28:57ZMolecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK110.1038/s41598-021-96817-32045-2322https://doaj.org/article/97627965dec141f385e331f0e5a399ac2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96817-3https://doaj.org/toc/2045-2322Abstract P21-activated kinases (PAKs) are serine/threonine protein kinase which have six different isoforms (PAK1–6). Of those, PAK1 is overexpressed in many cancers and considered to be a major chemotherapeutic target. Most of the developed PAK1 inhibitor drugs work as pan-PAK inhibitors and show undesirable toxicity due to having untargeted kinase inhibition activities. Selective PAK1 inhibitors are therefore highly desired and oncogenic drug hunters are trying to develop allosteric PAK1 inhibitors. We previously synthesized 1,2,3-triazolyl ester of ketorolac (15K) through click chemistry technique, which exhibits significant anti-cancer effects via inhibiting PAK1. Based on the selective anticancer effects of 15K against PAK1-dependent cancer cells, we hypothesize that it may act as an allosteric PAK1 inhibitor. In this study, computational analysis was done with 15K to explore its quantum chemical and thermodynamic properties, molecular interactions and binding stability with PAK1, physicochemical properties, ADMET, bioactivities, and druglikeness features. Molecular docking analysis demonstrates 15K as a potent allosteric ligand that strongly binds to a novel allosteric site of PAK1 (binding energy ranges – 8.6 to – 9.2 kcal/mol) and does not target other PAK isoforms; even 15K shows better interactions than another synthesized PAK1 inhibitor. Molecular dynamics simulation clearly supports the stable binding properties of 15K with PAK1 crystal. Density functional theory-based calculations reveal that it can be an active drug with high softness and moderate polarity, and ADMET predictions categorize it as a non-toxic drug as evidenced by in vitro studies with brine shrimp and fibroblast cells. Structure–activity relationship clarifies the role of ester bond and triazol moiety of 15K in establishing novel allosteric interactions. Our results summarize that 15K selectively inhibits PAK1 as an allosteric inhibitor and in turn shows anticancer effects without toxicity.Md ShahinozzamanSinthyia AhmedRashiduzzaman EmranShinkichi TawataNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Md Shahinozzaman Sinthyia Ahmed Rashiduzzaman Emran Shinkichi Tawata Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1
description	Abstract P21-activated kinases (PAKs) are serine/threonine protein kinase which have six different isoforms (PAK1–6). Of those, PAK1 is overexpressed in many cancers and considered to be a major chemotherapeutic target. Most of the developed PAK1 inhibitor drugs work as pan-PAK inhibitors and show undesirable toxicity due to having untargeted kinase inhibition activities. Selective PAK1 inhibitors are therefore highly desired and oncogenic drug hunters are trying to develop allosteric PAK1 inhibitors. We previously synthesized 1,2,3-triazolyl ester of ketorolac (15K) through click chemistry technique, which exhibits significant anti-cancer effects via inhibiting PAK1. Based on the selective anticancer effects of 15K against PAK1-dependent cancer cells, we hypothesize that it may act as an allosteric PAK1 inhibitor. In this study, computational analysis was done with 15K to explore its quantum chemical and thermodynamic properties, molecular interactions and binding stability with PAK1, physicochemical properties, ADMET, bioactivities, and druglikeness features. Molecular docking analysis demonstrates 15K as a potent allosteric ligand that strongly binds to a novel allosteric site of PAK1 (binding energy ranges – 8.6 to – 9.2 kcal/mol) and does not target other PAK isoforms; even 15K shows better interactions than another synthesized PAK1 inhibitor. Molecular dynamics simulation clearly supports the stable binding properties of 15K with PAK1 crystal. Density functional theory-based calculations reveal that it can be an active drug with high softness and moderate polarity, and ADMET predictions categorize it as a non-toxic drug as evidenced by in vitro studies with brine shrimp and fibroblast cells. Structure–activity relationship clarifies the role of ester bond and triazol moiety of 15K in establishing novel allosteric interactions. Our results summarize that 15K selectively inhibits PAK1 as an allosteric inhibitor and in turn shows anticancer effects without toxicity.
format	article
author	Md Shahinozzaman Sinthyia Ahmed Rashiduzzaman Emran Shinkichi Tawata
author_facet	Md Shahinozzaman Sinthyia Ahmed Rashiduzzaman Emran Shinkichi Tawata
author_sort	Md Shahinozzaman
title	Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1
title_short	Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1
title_full	Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1
title_fullStr	Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1
title_full_unstemmed	Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1
title_sort	molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15k) to be a novel allosteric modulator of the oncogenic kinase pak1
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/97627965dec141f385e331f0e5a399ac
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Molecular modelling approaches predicted 1,2,3-triazolyl ester of ketorolac (15K) to be a novel allosteric modulator of the oncogenic kinase PAK1

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