Journal of In Silico & In Vitro Pharmacology

Integrated In silico Docking and MoMA Simulation Approaches Reveal Withaferin A, Withalongolides A and B as Potent AldoKeto Reductase (AKR) 1C3 Inhibitors

Aldo-keto reductase family 1 member C3 (AKR1C3) is a steroidogenic enzyme and prospective drug target in leukemia, breast and prostate cancers. Overexpression of AKR1C3 can lead to the development of a variety of human cancers. Cancers that overexpress AKR1C3 exhibit chemotherapeutic resistance resulting in treatment failure and disease progression. Inhibition of AKR1C3 expression down-regulates cell proliferation in abiraterone-resistant prostate cancer cells. Therefore, the identification of a selective AKR1C3 inhibitor may reveal a novel strategy to combat drug resistance cancers. Recently, withaferin A (1) and other withanolides attracted attention as promising therapeutic candidates useful in treating a variety of cancers. Bioinformatic tools were utilized to identify the specific targets of different ligands. In silico predictions, modelling and dynamic simulations based on the crystal structure of AKR1C3 and ligands were performed. Active molecular docking studies using AutoDock Vina software suggested that withaferin A, withalongolide A and withalongolide B are novel inhibitors of AKR1C3 with binding affinities of -11.2, -12.5 and -13.1 kcal/mol, respectively. Of the ligands investigated in this study, withalongolide B produced the greatest AKR1C3 binding affinity. The data suggests that withalongolide B could be utilized as potent lead compound to probe cancers that utilize AKR1C3 overexpression for drug- resistance, such as abiraterone-resistant prostate cancer.

Author(s):

Vadapalli J, Gallagher R, Vanam A, Motohashi N and Gollapudi R*

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