Computational modeling studies reveal the origin of the binding preference of 3‐(3,4‐di hydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over its isoforms

As a key regulator for hormone activity, human aldo‐keto reductase family 1 member C3 (AKR1C3) plays crucial roles in the occurrence of various hormone‐dependent or independent malignancies. It is a promising target for treating castration‐resistant prostate cancer (CRPC). However, the development of AKR1C3 specific inhibitors remains challenging due to the high sequence similarity to its isoform AKR1C2. Here, we performed a combined in silico study to illuminate the inhibitory preference of 3‐(3,4‐dihydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over AKR1C2, of which compound 38 can achieve up to 5000‐fold anti‐AKR1C3 selectivity. Our umbrella sampling (US) simulations together with end‐point binding free energy calculation MM/GBSA uncover that the high inhibition selectivity originates from the different binding modes, namely “Inward” and “Outward,” of this compound series in AKR1C3 and AKR1C2, respectively. In AKR1C3/38, the tetrahydroquinoline moiety of 38 is accommodated inside the SP1 pocket and interacts favorably with surrounding residues, while, in AKR1C2/38, the SP1 pocket is too small to hold the bulky tetrahydroquinoline group that instead moves out of the pocket with 38 transitioning from an “Inward” to an “Outward” state. Further 3D‐QSAR and energy decomposition analyses suggest that SP1 in AKR1C3 prefers to bind with a rigid bicyclic moiety and the modification of the R(3) group has important implication for the compound's activity. This work is the first attempt to elucidate the selectivity mechanism of inhibitors toward AKR1C3 at the atomic level, which is anticipated to propel the development of next‐generation AKR1C3 inhibitors with enhanced efficacy and reduced “off‐target” effect for CRPC therapy.