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

Abstract

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 R3 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.

Design and Evaluation of NSAID Derivatives as AKR1C3 Inhibitors for Breast Cancer Treatment through Computer-Aided Drug Design and In Vitro Analysis

“…Compared to commercial celecoxib, 10 of the 20 proposed structures had affinity values (SBVS) that were equally or even more harmful for AKR1C3. The preferred interactions between AKR1C3 and 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids were determined to be Tyr216, Phe311, Tyr219, and Hys119 in previous studies [30,31]. Interactions were preserved, and analogs C-6 and C-7 enhanced the number of hydrophobic interactions compared to our developed counterparts, which may cause an increase in interaction energy (SI).…”

“…Interactions were preserved, and analogs C-6 and C-7 enhanced the number of hydrophobic interactions compared to our developed counterparts, which may cause an increase in interaction energy (SI). Keeping with LVBS, six analogs of all those created had lower IC 50 predicted by ANN compared to celecoxib (Table 1, entries [25][26][27][28][29][30]. The fact that celecoxib's whole pharmacophoric grouping was kept and the auxophoric chain of the sulfonamide was explicitly altered, which has little to no impact on the calculation of the descriptors between the analogs, accounts for the similarity of the anticipated IC 50 values in most created analogs.…”

“…As a result, six analogs belonging to the N-(phenylsulfonyl) alkylamides were produced (modification 2, Scheme 1). We selected this group's lowest IC 50 (Table 1, entries [29][30] values. The toxicity of a substance was predicted by analyzing two rodent carcinogenicity studies and a mutagenicity assay using S. typhimurium (Table 3).…”

AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications

“…On the other hand, SP1 in AKR1C2 isoform is described as smaller than in AKR1C3, thus unable to tolerate the same hindered substituents accepted by C3. 40 Figure 3 and Figure S1 highlight in green the residues that are different in AKR1C3 and C2 binding site. For a focused analysis on the volume difference between SP1 in AKR1C3 and C2, see Figure S2.…”

“…Specifically, SP1 of AKR1C3 is characterized by multiple nonconserved residues, outlining a wide area that can favorably host relatively bulky groups. On the other hand, SP1 in AKR1C2 isoform is described as smaller than in AKR1C3, thus unable to tolerate the same hindered substituents accepted by C3 Figure and Figure S1 highlight in green the residues that are different in AKR1C3 and C2 binding site.…”