Exploration of Novel MTH1 Inhibitors Using Fragment-Based De Novo Design, Virtual Screening, and Reverse Virtual Screening Methods

Abstract

MTH1 (MutT homologue 1, NUDT1), a member of the Nudix phosphohydrolase superfamily of enzymes, was speculated to contribute to hampering tumor growth based on a number of validation experiments. Based on the crystal structure of MTH1, de novo design was employed to construct a series of new MTH1 inhibitors by means of fragment-based strategy. ADMET (absorption, distribution, metabolism, excretion, toxicity) were used to assess the pharmacokinetic profiles; pharmacophore screening and molecular docking were carried out to obtain 9 candidate molecules. Then, molecular dynamic (MD) simulations were performed to learn the stability of receptor–ligand complexes, which have the lowest binding energy in docking, and the binding model was analyzed. Finally, using reverse virtual screening, potential targets of query compounds, especially those enzymes participating in various cancer-related pathways, were found. The results provide theoretical basis for the design of more potent MTH1 inhibitors.