Finding inhibitors for PCSK9 using computational methods.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key targets for atherosclerosis drug development as its binding with low-density lipoprotein receptor leads to atherosclerosis. The protein-ligand interaction helps to understand the actual mechanism for the pharmacological action....

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Autores principales:	Rida Zainab, Afshan Kaleem, Michał B Ponczek, Roheena Abdullah, Mehwish Iqtedar, Daniel C Hoessli
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c99e97c78a2c47ea9969b0b623c9f424
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spelling	oai:doaj.org-article:c99e97c78a2c47ea9969b0b623c9f4242021-12-02T20:18:41ZFinding inhibitors for PCSK9 using computational methods.1932-620310.1371/journal.pone.0255523https://doaj.org/article/c99e97c78a2c47ea9969b0b623c9f4242021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0255523https://doaj.org/toc/1932-6203Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key targets for atherosclerosis drug development as its binding with low-density lipoprotein receptor leads to atherosclerosis. The protein-ligand interaction helps to understand the actual mechanism for the pharmacological action. This research aims to discover the best inhibitory candidates targeting PCSK9. To start with, reported ACE inhibitors were incorporated into pharmacophore designing using PharmaGist to produce pharmacophore models. Selected models were later screened against the ZINC database using ZINCPHARMER to define potential drug candidates that were docked with the target protein to understand their interactions. Molecular docking revealed the top 10 drug candidates against PCSK9, with binding energies ranging from -9.8 kcal·mol-1 to -8.2 kcal·mol-1, which were analyzed for their pharmacokinetic properties and oral bioavailability. Some compounds were identified as plant-derived compounds like (S)-canadine, hesperetin or labetalol (an antihypertensive drug). Molecular dynamics results showed that these substances formed stable protein-ligand complexes. (S)-canadine-PCSK9 complex was the most stable with the lowest RMSD. It was concluded that (S)-canadine may act as a potential inhibitor against atherosclerosis for the development of new PCSK9 inhibitory drugs in future in vitro research.Rida ZainabAfshan KaleemMichał B PonczekRoheena AbdullahMehwish IqtedarDaniel C HoessliPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0255523 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rida Zainab Afshan Kaleem Michał B Ponczek Roheena Abdullah Mehwish Iqtedar Daniel C Hoessli Finding inhibitors for PCSK9 using computational methods.
description	Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key targets for atherosclerosis drug development as its binding with low-density lipoprotein receptor leads to atherosclerosis. The protein-ligand interaction helps to understand the actual mechanism for the pharmacological action. This research aims to discover the best inhibitory candidates targeting PCSK9. To start with, reported ACE inhibitors were incorporated into pharmacophore designing using PharmaGist to produce pharmacophore models. Selected models were later screened against the ZINC database using ZINCPHARMER to define potential drug candidates that were docked with the target protein to understand their interactions. Molecular docking revealed the top 10 drug candidates against PCSK9, with binding energies ranging from -9.8 kcal·mol-1 to -8.2 kcal·mol-1, which were analyzed for their pharmacokinetic properties and oral bioavailability. Some compounds were identified as plant-derived compounds like (S)-canadine, hesperetin or labetalol (an antihypertensive drug). Molecular dynamics results showed that these substances formed stable protein-ligand complexes. (S)-canadine-PCSK9 complex was the most stable with the lowest RMSD. It was concluded that (S)-canadine may act as a potential inhibitor against atherosclerosis for the development of new PCSK9 inhibitory drugs in future in vitro research.
format	article
author	Rida Zainab Afshan Kaleem Michał B Ponczek Roheena Abdullah Mehwish Iqtedar Daniel C Hoessli
author_facet	Rida Zainab Afshan Kaleem Michał B Ponczek Roheena Abdullah Mehwish Iqtedar Daniel C Hoessli
author_sort	Rida Zainab
title	Finding inhibitors for PCSK9 using computational methods.
title_short	Finding inhibitors for PCSK9 using computational methods.
title_full	Finding inhibitors for PCSK9 using computational methods.
title_fullStr	Finding inhibitors for PCSK9 using computational methods.
title_full_unstemmed	Finding inhibitors for PCSK9 using computational methods.
title_sort	finding inhibitors for pcsk9 using computational methods.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/c99e97c78a2c47ea9969b0b623c9f424
work_keys_str_mv	AT ridazainab findinginhibitorsforpcsk9usingcomputationalmethods AT afshankaleem findinginhibitorsforpcsk9usingcomputationalmethods AT michałbponczek findinginhibitorsforpcsk9usingcomputationalmethods AT roheenaabdullah findinginhibitorsforpcsk9usingcomputationalmethods AT mehwishiqtedar findinginhibitorsforpcsk9usingcomputationalmethods AT danielchoessli findinginhibitorsforpcsk9usingcomputationalmethods
_version_	1718374251768053760

Finding inhibitors for PCSK9 using computational methods.

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