Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics.

Mitogen-activated protein kinase 1 (MAPK1) is a serine/threonine kinase that plays a crucial role in the MAP kinase signaling transduction pathway. This pathway plays a crucial role in various cellular processes, including cell proliferation, differentiation, adhesion, migration, and survival. Besid...

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Main Authors: Md Nayab Sulaimani, Shazia Ahmed, Farah Anjum, Taj Mohammad, Anas Shamsi, Ravins Dohare, Md Imtaiyaz Hassan
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2025-01-01
Series:PLoS ONE
Online Access:https://doi.org/10.1371/journal.pone.0311954
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author Md Nayab Sulaimani
Shazia Ahmed
Farah Anjum
Taj Mohammad
Anas Shamsi
Ravins Dohare
Md Imtaiyaz Hassan
author_facet Md Nayab Sulaimani
Shazia Ahmed
Farah Anjum
Taj Mohammad
Anas Shamsi
Ravins Dohare
Md Imtaiyaz Hassan
author_sort Md Nayab Sulaimani
collection DOAJ
description Mitogen-activated protein kinase 1 (MAPK1) is a serine/threonine kinase that plays a crucial role in the MAP kinase signaling transduction pathway. This pathway plays a crucial role in various cellular processes, including cell proliferation, differentiation, adhesion, migration, and survival. Besides, many chemotherapeutic drugs targeting the MAPK pathway are used in clinical practice, and novel inhibitors of MAPK1 with improved specificity and efficacy are required. Hence, targeting MAPK1 can be crucial to control metastasis in cancer therapeutics. In this study, we utilized a structure-guided virtual screening approach to screen a library of thousands of natural compounds from the ZINC database. The Lipinski rule of five (RO5) was used as a criterion for the primary selection of natural compounds. The screened compounds were prioritized based on their binding affinity, docking scores, and specificity towards the kinase domain of MAPK1 during the molecular docking process. Subsequently, the selected hits underwent rigorous screening that included the identification of potential pan-assay interference compounds (PAINS), ADMET evaluation, and prediction of pharmacological activities using PASS analysis. Afterwards, we performed a comprehensive interaction analysis to explore the binding prototypes of the screened molecules with the key residues within the MAPK1 kinase domain. Finally, selected molecules underwent extensive all-atom molecular dynamics (MD) simulations for a time duration of 200 nanoseconds. The study pinpointed three natural compounds with ZINC database IDs ZINC0209285, ZINC02130647, and ZINC02133691 as potential inhibitors of MAPK1. The study highlights that these compounds could be explored further in preclinical and clinical investigations to develop anticancer therapeutics.
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spelling doaj-art-f3874d4415b9413b889826308492f2f52025-02-05T05:32:14ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01201e031195410.1371/journal.pone.0311954Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics.Md Nayab SulaimaniShazia AhmedFarah AnjumTaj MohammadAnas ShamsiRavins DohareMd Imtaiyaz HassanMitogen-activated protein kinase 1 (MAPK1) is a serine/threonine kinase that plays a crucial role in the MAP kinase signaling transduction pathway. This pathway plays a crucial role in various cellular processes, including cell proliferation, differentiation, adhesion, migration, and survival. Besides, many chemotherapeutic drugs targeting the MAPK pathway are used in clinical practice, and novel inhibitors of MAPK1 with improved specificity and efficacy are required. Hence, targeting MAPK1 can be crucial to control metastasis in cancer therapeutics. In this study, we utilized a structure-guided virtual screening approach to screen a library of thousands of natural compounds from the ZINC database. The Lipinski rule of five (RO5) was used as a criterion for the primary selection of natural compounds. The screened compounds were prioritized based on their binding affinity, docking scores, and specificity towards the kinase domain of MAPK1 during the molecular docking process. Subsequently, the selected hits underwent rigorous screening that included the identification of potential pan-assay interference compounds (PAINS), ADMET evaluation, and prediction of pharmacological activities using PASS analysis. Afterwards, we performed a comprehensive interaction analysis to explore the binding prototypes of the screened molecules with the key residues within the MAPK1 kinase domain. Finally, selected molecules underwent extensive all-atom molecular dynamics (MD) simulations for a time duration of 200 nanoseconds. The study pinpointed three natural compounds with ZINC database IDs ZINC0209285, ZINC02130647, and ZINC02133691 as potential inhibitors of MAPK1. The study highlights that these compounds could be explored further in preclinical and clinical investigations to develop anticancer therapeutics.https://doi.org/10.1371/journal.pone.0311954
spellingShingle Md Nayab Sulaimani
Shazia Ahmed
Farah Anjum
Taj Mohammad
Anas Shamsi
Ravins Dohare
Md Imtaiyaz Hassan
Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics.
PLoS ONE
title Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics.
title_full Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics.
title_fullStr Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics.
title_full_unstemmed Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics.
title_short Structure-guided identification of mitogen-activated protein kinase-1 inhibitors towards anticancer therapeutics.
title_sort structure guided identification of mitogen activated protein kinase 1 inhibitors towards anticancer therapeutics
url https://doi.org/10.1371/journal.pone.0311954
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