Abstract

MOLECULAR DOCKING DOES NOT PREDICT THERAPEUTIC VIABILITY: A CASE STUDY OF ARISTOLOCHIC ACIDS IN UROTHELIAL CANCER TARGETS

*Sachin Kumar, Dr. A. Bala Subramaniam

Abstract

Aristolochic acids I (AA-I) and II (AA-II), bioactive constituents of Aristolochia indica, exhibit cytotoxic activity but are also well-established nephrotoxins and human carcinogens. This study evaluated their molecular interaction profiles with key cancer-associated proteins and assessed their therapeutic relevance using an integrated computational framework. Molecular docking was performed using the Glide Extra Precision (XP) protocol against multiple oncogenic targets, including PD-L1, FGFR3, PI3Kα, AKT1, mTOR, and Bcl-xL. Comparative analysis was conducted for all targets for which paired docking outputs were available. In parallel, in silico ADME and toxicological assessments were performed to contextualize docking outcomes. Both compounds demonstrated moderate to weak binding affinities across most targets, with the strongest interaction observed for AA-I against PI3Kα (−7.757 kcal/mol). However, the predicted binding modes lacked key structural features required for selective inhibition, including canonical hinge-binding interactions in kinase targets and appropriate interface complementarity for protein–protein interaction disruption. ADME evaluation indicated unfavorable pharmacokinetic properties, including low predicted gastrointestinal absorption, high plasma protein binding, and preferential renal accumulation. Importantly, both compounds undergo metabolic activation to form DNA-reactive intermediates, leading to persistent DNA adduct formation and mutational signatures associated with urothelial carcinogenesis. Overall, these findings demonstrate that moderate docking scores do not translate into therapeutic viability. The biological activity of aristolochic acids is dominated by genotoxicity rather than selective protein inhibition, rendering them unsuitable as anticancer agents in their native form.

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