title: 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 IC50values 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 hindrance than a methyl group in TH287. So TH588 has a slightly reduced inhibitory activity compared to TH287. TH650 induces greater conformation fluctuations than TH588 and the binding site adopts an opening state, which is caused by the large bulk of oxetanyl group and the interference of solvent on the oxetanyl substituent, leading to the lowest inhibitory activity. Thus, the inhibitory activity follows a TH287 > TH588 > TH650 trend, which well matches with the experimental finding.
authors.affiliation: State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530004, People's Republic of China.|College of Life Science and Technology, Guangxi University, Nanning 530004, People's Republic of China.|School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, People's Republic of China.
authors.forename: Mian
authors.initials: M
authors.lastname: Wang
authors.affiliation: School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, People's Republic of China.
authors.forename: Shuilian
authors.initials: S
authors.lastname: Zhou
authors.affiliation: School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, People's Republic of China.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi University, Nanning 530004, People's Republic of China.|College of Life Science and Technology, Guangxi University, Nanning 530004, People's Republic of China.
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Liang
authors.affiliation: School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, People's Republic of China.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009038:Motion; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D025341:Principal Component Analysis; D013816:Thermodynamics
chemical_list: D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes