%0 Journal Article
%T Accelerating the identification of subtype selective inhibitors via Three-Dimensional Biologically Relevant Spectrum (BRS-3D): The monoamine oxidase subtypes as a case study.
%A Wang D
%A Chen N
%A Taranto AG
%A Jin Y
%A Wen C
%A Kong DX
%J Bioorg Chem
%V 106
%N 0
%D 01 2021
%M 33280834
%F 5.307
%R 10.1016/j.bioorg.2020.104503
%X Subtype-selective drugs are of great therapeutic importance as they are expected to be more effective and with less side-effects. However, discovery of subtype selective inhibitors was hampered by the high similarity of the binding sites within subfamilies. In this study, we further evaluated the applicability of "Three-Dimensional Biologically Relevant Spectrum (BRS-3D)" for the identification of subtype-selective inhibitors. A case study was performed on monoamine oxidase, which has two subtypes related to distinct diseases. The inhibitory activity against MAO-A/B of 347 compounds experimentally tested in this research was reported. Compound M124 (5H-thiazolo[3,2-a]pyrimidin-5-one) with IC50 less than 100 nM (SI = 23) was selected as a probe to investigate the structure selectivity relationship. Similarity search led to the identification of compound M229 and M249 with IC50 values of 7.4 nM, 4 nM and acceptable selectivity index over MAO-A (M229 SI > 1351, M249 SI > 2500). The molecular basis for subtype selectivity was explored through docking study and attention based DNN model. Additionally, in silico ADME properties were characterized. Accordingly, it is found that BRS-3D is a robust method for subtype selectivity in the early stage of drug discovery and the compounds reported here can be promising leads for further experimental analysis.