Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1.

ABSTRACT: MTH1 can hydrolyze oxidized nucleotides and is required for cancer survival. The IC₅₀ values were 0.8 nM for TH287 with a methyl substitution, 5.0 nM for TH588 with a cyclopropyl substitution, and 2.1 μM for TH650 with an oxetanyl substitution. Thus, it is very significant to understand inhibitory mechanisms of these structurally similar compounds against MTH1 and influences of the substituent on the bioactivities. Our MD researches indicate that TH287 maintains significant hydrogen bonds with Asn33 and Asp119, stabilizes the binding site, and induces MTH1 adopt a closed motion, leading to a high inhibitory activity. When bound with TH588, the binding site can be partially stabilized and take a semi-closed state, which is because the cyclopropyl group in TH588 has larger steric

SUBMITTER: Wang M 

PROVIDER: S-EPMC5225434 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature