Understanding the Pyrimethamine drug resistance mechanism via combined molecular dynamics and dynamic residue network analysis:

Amusengeri, Arnold; Tata, Rolland B; Tastan Bishop, Özlem

Title: Understanding the Pyrimethamine drug resistance mechanism via combined molecular dynamics and dynamic residue network analysis:
Creator: Amusengeri, Arnold
Creator: Tata, Rolland B
Creator: Tastan Bishop, Özlem
Date Issued: 2020
Date: 2020
Type: text
Type: article
Identifier: http://hdl.handle.net/10962/163022
Identifier: vital:41005
Identifier: https://doi.org/10.3390/molecules25040904
Description: In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity.
Format: 25 pages
Format: pdf
Language: English
Relation: Molecules
Relation: Amusengeri, A., Tata, R.B. and Tastan Bishop, Ö., 2020. Understanding the Pyrimethamine drug resistance mechanism via combined molecular dynamics and dynamic residue network analysis. Molecules, 25(4), p.904
Relation: Molecules volume 25 number 4 1 24 February 2020 1420-3049
Rights: Publisher
Rights: Use of this resource is governed by the terms and conditions of the MDPI Open Access Statement (https://www.int-res.com/journals/terms-of-use/)

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Tastan Bishop, Ozlem (Prof)

RU Research Unit in Bioinformatics (RUBi)

RU Department of Biochemistry, Microbiology and Biotechnology

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