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.

亚型选择性药物具有重要的治疗意义，因为它们预计更有效且副作用更少。然而，亚家族内结合位点的高度相似性阻碍了亚型选择性抑制剂的发现。在本研究中，我们进一步评估了“三维生物相关光谱（BRS-3D）”在亚型选择性抑制剂鉴定中的适用性。对单胺氧化酶进行了案例研究，单胺氧化酶有两种与不同疾病相关的亚型。报告了本研究中实验测试的 347 种化合物对 MAO-A/B 的抑制活性。化合物M124（5H-噻唑并[3,2-a]嘧啶-5-one），IC ₅₀选择小于 100 nM (SI=23) 作为探针来研究结构选择性关系。相似性搜索导致化合物M229和M249的鉴定，其 IC ₅₀值为 7.4 nM、4 nM 和可接受的选择性指数超过 MAO-A（M229 SI > 1351，M249 SI > 2500）。通过对接研究和基于注意力的 DNN 模型探索了亚型选择性的分子基础。此外，还表征了计算机ADME 特性。因此，发现 BRS-3D 是药物发现早期亚型选择性的可靠方法，这里报道的化合物可以作为进一步实验分析的有希望的线索。