Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations

The G-protein coupled receptor, GPR120, has ubiquitous expression and multifaceted roles in modulating metabolic and anti-inflammatory processes. Recent implications of its role in cancer progression have presented GPR120 as an attractive oncogenic drug target. GPR120 gene knockdown in breast cancer...

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Autores principales:	Ajay Pal, James F. Curtin, Gemma K. Kinsella
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Molecular dynamics Pharmacophore screening G-protein coupled receptor GPR120 Biotechnology TP248.13-248.65
Acceso en línea:	https://doaj.org/article/fcf19c2399204e4fa659764299d2f8fb
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spelling	oai:doaj.org-article:fcf19c2399204e4fa659764299d2f8fb2021-11-20T05:05:23ZStructure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations2001-037010.1016/j.csbj.2021.11.005https://doaj.org/article/fcf19c2399204e4fa659764299d2f8fb2021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2001037021004700https://doaj.org/toc/2001-0370The G-protein coupled receptor, GPR120, has ubiquitous expression and multifaceted roles in modulating metabolic and anti-inflammatory processes. Recent implications of its role in cancer progression have presented GPR120 as an attractive oncogenic drug target. GPR120 gene knockdown in breast cancer studies revealed a role of GPR120-induced chemoresistance in epirubicin and cisplatin-induced DNA damage in tumour cells. Higher expression and activation levels of GPR120 is also reported to promote tumour angiogenesis and cell migration in colorectal cancer. Some agonists targeting GPR120 have been reported, such as TUG891 and Compound39, but to date development of small-molecule inhibitors of GPR120 is limited.Herein, following homology modelling of the receptor a pharmacophore hypothesis was derived from 300 ns all-atomic molecular dynamics (MD) simulations on apo, TUG891-bound and Compound39-bound GPR120S (short isoform) receptor models embedded in a water solvated lipid bilayer system. We performed comparative MD analysis on protein–ligand interactions between the two agonist and apo simulations on the stability of the “ionic lock” – a Class A GPCRs characteristic of receptor activation and inactivation. The detailed analysis predicted that ligand interactions with W277 and N313 are critical to conserve the “ionic-lock” conformation (R136 of Helix 3) and prevent GPR120S receptor activation. The results led to generation of a W277 and N313 focused pharmacophore hypothesis and the screening of the ZINC15 database using ZINCPharmer through the structure-based pharmacophore.100 ns all-atomic molecular dynamics (MD) simulations were performed on 9 small molecules identified and Cpd 9, (2-hydroxy-N-{4-[(6-hydroxy-2-methylpyrimidin-4-yl) amino] phenyl} benzamide) was predicted to be a small-molecule GPR120S antagonist. The conformational results from the collective all-atomic MD analysis provided structural information for further identification and optimisation of novel druggable inhibitors of GPR120S using this rational design approach, which could have future potential for anti-cancer drug development studies.Ajay PalJames F. CurtinGemma K. KinsellaElsevierarticleMolecular dynamicsPharmacophore screeningG-protein coupled receptor GPR120BiotechnologyTP248.13-248.65ENComputational and Structural Biotechnology Journal, Vol 19, Iss , Pp 6050-6063 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Molecular dynamics Pharmacophore screening G-protein coupled receptor GPR120 Biotechnology TP248.13-248.65
spellingShingle	Molecular dynamics Pharmacophore screening G-protein coupled receptor GPR120 Biotechnology TP248.13-248.65 Ajay Pal James F. Curtin Gemma K. Kinsella Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations
description	The G-protein coupled receptor, GPR120, has ubiquitous expression and multifaceted roles in modulating metabolic and anti-inflammatory processes. Recent implications of its role in cancer progression have presented GPR120 as an attractive oncogenic drug target. GPR120 gene knockdown in breast cancer studies revealed a role of GPR120-induced chemoresistance in epirubicin and cisplatin-induced DNA damage in tumour cells. Higher expression and activation levels of GPR120 is also reported to promote tumour angiogenesis and cell migration in colorectal cancer. Some agonists targeting GPR120 have been reported, such as TUG891 and Compound39, but to date development of small-molecule inhibitors of GPR120 is limited.Herein, following homology modelling of the receptor a pharmacophore hypothesis was derived from 300 ns all-atomic molecular dynamics (MD) simulations on apo, TUG891-bound and Compound39-bound GPR120S (short isoform) receptor models embedded in a water solvated lipid bilayer system. We performed comparative MD analysis on protein–ligand interactions between the two agonist and apo simulations on the stability of the “ionic lock” – a Class A GPCRs characteristic of receptor activation and inactivation. The detailed analysis predicted that ligand interactions with W277 and N313 are critical to conserve the “ionic-lock” conformation (R136 of Helix 3) and prevent GPR120S receptor activation. The results led to generation of a W277 and N313 focused pharmacophore hypothesis and the screening of the ZINC15 database using ZINCPharmer through the structure-based pharmacophore.100 ns all-atomic molecular dynamics (MD) simulations were performed on 9 small molecules identified and Cpd 9, (2-hydroxy-N-{4-[(6-hydroxy-2-methylpyrimidin-4-yl) amino] phenyl} benzamide) was predicted to be a small-molecule GPR120S antagonist. The conformational results from the collective all-atomic MD analysis provided structural information for further identification and optimisation of novel druggable inhibitors of GPR120S using this rational design approach, which could have future potential for anti-cancer drug development studies.
format	article
author	Ajay Pal James F. Curtin Gemma K. Kinsella
author_facet	Ajay Pal James F. Curtin Gemma K. Kinsella
author_sort	Ajay Pal
title	Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations
title_short	Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations
title_full	Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations
title_fullStr	Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations
title_full_unstemmed	Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations
title_sort	structure based prediction of a novel gpr120 antagonist based on pharmacophore screening and molecular dynamics simulations
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/fcf19c2399204e4fa659764299d2f8fb
work_keys_str_mv	AT ajaypal structurebasedpredictionofanovelgpr120antagonistbasedonpharmacophorescreeningandmoleculardynamicssimulations AT jamesfcurtin structurebasedpredictionofanovelgpr120antagonistbasedonpharmacophorescreeningandmoleculardynamicssimulations AT gemmakkinsella structurebasedpredictionofanovelgpr120antagonistbasedonpharmacophorescreeningandmoleculardynamicssimulations
_version_	1718419636117045248

Structure based prediction of a novel GPR120 antagonist based on pharmacophore screening and molecular dynamics simulations

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