1. Ensemble-based virtual screening of African natural products to target human thymidylate synthase.
- Author
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Mteremko D, Chilongola J, Paluch AS, and Chacha M
- Subjects
- Humans, Molecular Docking Simulation, Ligands, Protein Binding, Thymidylate Synthase chemistry
- Abstract
Human thymidylate synthase (hTS) is a validated drug target for chemotherapy. A virtual screening experiment was used to prioritize a list of compounds from African Natural Products Databases docked against the orthosteric binding pocket of hTS. Consensus scores of binding affinities from ensemble-based virtual screening, hydrated docking and MM-PBSA calculations ranked compounds NEA4433 and NEA4434 as the best candidates owing to binding affinity scores in the picomolar order, their excellent ADMET profiles and the good stability of the protein-ligand complexes formed. The current study demonstrates the role of water in small molecule binding to hTS in mediating protein-ligand interactions. Similarly, the robust ensemble docking (relaxed scheme complex) ranked NEA4433 and NEA4434 as the best candidates. Furthermore, the best candidates prioritized were shown to strongly interact with the same residues that interacted with hTS substrate and cofactor., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Denis Mteremko reports financial support was provided by The World Bank, through The Africa Centre for Research, Agricultural Advancement, Teaching Excellence and Sustainability (CREATES)., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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