Force Field Parameters for Fe2+ 4S2− 4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies

Tendwa, Maureen B; Chebon-Bore, Lorna; Lobb, Kevin A; Musyoka, Thommas M; Taştan Bishop, Özlem

Title: Force Field Parameters for Fe2+ 4S2− 4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies
Creator: Tendwa, Maureen B
Creator: Chebon-Bore, Lorna
Creator: Lobb, Kevin A
Creator: Musyoka, Thommas M
Creator: Taştan Bishop, Özlem
Subject: To be catalogued
Date Issued: 2021
Date: 2021
Type: text
Type: article
Identifier: http://hdl.handle.net/10962/451078
Identifier: vital:75016
Identifier: xlink:href="https://doi.org/10.3390/molecules26102929 "
Description: The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe2+4S2−4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2−4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe2+4S2−4 cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.
Format: computer
Format: online resource
Format: application/pdf
Format: 1 online resource (27 pages)
Format: pdf
Publisher: MDPI
Language: English
Relation: Molecules
Relation: Tendwa, M.B., Chebon-Bore, L., Lobb, K., Musyoka, T.M. and Tastan Bishop, Ö., 2021. Force Field Parameters for Fe2+ 4S2− 4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies. Molecules, 26(10), p.2929
Relation: Molecules volume 26 number 10 p. 2929 2021 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/)
Rights: Open Access

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Tastan Bishop, Ozlem (Prof)

RU Research Unit in Bioinformatics (RUBi)

Lobb, Kevin Allan (Assoc Prof)

RU Department of Chemistry

RU Department of Biochemistry, Microbiology and Bioinformatics

SDG 03. Good Health and Well-Being

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