Functional restoration of conformational (R175H) and contact (R273H) mutant p53 by Bacillus-derived Hydroxymycotrienin A in non-small cell lung cancer: a computational approach

Abstract

Introduction The TP53 mutations in Non-Small Cell Lung Cancer (NSCLC) remain a formidable clinical challenge. Current strategies, using the covalent binder APR-246, are limited by off-target toxicity and resistance. Methods This study screens 1,580 Bacillus-derived metabolites to identify novel non-covalent pharmacological chaperones for native, conformational (R175H), and contact (R273H) p53 mutants. Virtual screening, ADMET profiling, molecular docking, extended 500 ns Molecular Dynamics (MD) simulations and Principal Component Analysis, against experimental anti-cancer drug APR-246, and top hit compounds. Results Hydroxymycotrienin A emerged as the potential candidate, demonstrating thermodynamic superiority with binding affinities of −6.63 kcal/mol (R175H) and −6.57 kcal/mol (R273H), demonstrated significant superior non covalent docking affinity compared to APR-246 parent scaffold (approximately −3.5 kcal/mol) in the mutated p53 protein, suggesting a direct pharmacological chaperone activity. Unlike the covalent alkylating mechanism of APR-246, Hydroxymycotrienin A utilizes a non-covalent network to chaperone the mutant p53. MD simulations revealed that Hydroxymycotrienin A acted as a structural stabilizer for the conformational mutant R175H by suppressing atomic fluctuations within the L2 loop and reducing overall structural deviations. In the contact mutant R273H, the ligand stabilized the DNA-binding interface while maintaining favorable conformational dynamics without introducing steric clashes. Discussion ADMET profiling predicts high bioavailability and a non-toxic safety profile, characterizing Hydroxymycotrienin A as a promising, bioavailable ‘privileged scaffold’ that offers a non-covalent therapeutic strategy for NSCLC. By restoring p53 function, this study addresses Sustainable Development Goals Target 3.4 to reduce premature mortality from non-communicable diseases. However, future in vitro and in vivo studies are required to validate the efficacy of these compounds.