Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L.

Autor: Jha V; Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden.; School of Pharmacy and Medical Sciences, Faculty of Life Sciences, Institute of Cancer Therapeutics, University of Bradford, Bradford, BD71DP, UK., Eriksson LA; Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30, Göteborg, Sweden. leif.eriksson@chem.gu.se.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Sep 10; Vol. 14 (1), pp. 21073. Date of Electronic Publication: 2024 Sep 10.
DOI: 10.1038/s41598-024-71879-1
Abstrakt: The mitochondrial enzyme methylenetetrahydrofolate dehydrogenase (MTHFD2) is involved in purine and thymidine synthesis via 1C metabolism. MTHFD2 is exclusively overexpressed in cancer cells but absent in most healthy adult human tissues. However, the two close homologs of MTHFD2 known as MTHFD1 and MTHFD2L are expressed in healthy adult human tissues and share a great structural resemblance to MTHFD2 with 54% and 89% sequence similarity, respectively. It is therefore notably challenging to find selective inhibitors of MTHFD2 due to the structural similarity, in particular protein binding site similarity with MTHFD1 and MTHFD2L. Tricyclic coumarin-based compounds (substrate site binders) and xanthine derivatives (allosteric site binders) are the only selective inhibitors of MTHFD2 reported till date. Nanomolar potent diaminopyrimidine-based inhibitors of MTHFD2 have been reported recently, however, they also demonstrate significant inhibitory activities against MTHFD1 and MTHFD2L. In this study, we have employed extensive computational modeling involving molecular docking and molecular dynamics simulations in order to investigate the binding modes and key interactions of diaminopyrimidine-based inhibitors at the substrate binding sites of MTHFD1, MTHFD2 and MTHFD2L, and compare with the tricyclic coumarin-based selective MTHFD2 inhibitor. The outcomes of our study provide significant insights into desirable and undesirable structural elements for rational structure-based design of new and selective inhibitors of MTHFD2 against cancer.
(© 2024. The Author(s).)
Databáze: MEDLINE
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