Exploring Proteus mirabilis methionine tRNA synthetase active site: homology model construction, molecular dynamics, pharmacophore and docking validation

Elbaramawi, Samar S., Eissa, Ahmed G., Noureldin, Nada A. and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2023. Exploring Proteus mirabilis methionine tRNA synthetase active site: homology model construction, molecular dynamics, pharmacophore and docking validation. Pharmaceuticals 16 (9) , 1263. 10.3390/ph16091263

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Abstract

Currently, the treatment of Proteus mirabilis infections is considered to be complicated as the organism has become resistant to numerous antibiotic classes. Therefore, new inhibitors should be developed, targeting bacterial molecular functions. Methionine tRNA synthetase (MetRS), a member of the aminoacyl-tRNA synthetase family, is essential for protein biosynthesis offering a promising target for novel antibiotics discovery. In the context of computer-aided drug design (CADD), the current research presents the construction and analysis of a comparative homology model for P. mirabilis MetRS, enabling development of novel inhibitors with greater selectivity. Molecular Operating Environment (MOE) software was used to build a homology model for P. mirabilis MetRS using Escherichia coli MetRS as a template. The model was evaluated, and the active site of the target protein predicted from its sequence using conservation analysis. Molecular dynamic simulations were performed to evaluate the stability of the modeled protein structure. In order to evaluate the predicted active site interactions, methionine (the natural substrate of MetRS) and several inhibitors of bacterial MetRS were docked into the constructed model using MOE. After validation of the model, pharmacophore-based virtual screening for a systemically prepared dataset of compounds was performed to prove the feasibility of the proposed model, identifying possible parent compounds for further development of MetRS inhibitors against P. mirabilis.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	MDPI
Date of First Compliant Deposit:	10 October 2023
Date of Acceptance:	1 September 2023
Last Modified:	10 Oct 2023 14:16
URI:	https://orca.cardiff.ac.uk/id/eprint/163095

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