VIRTUAL SCREENING OF PHTHALIMIDE-BASED INHIBITORS TO OVERCOME PROSTATE CANCER RESISTANT DRUGS

Abstract

Despite the successes of traditional androgen-deprivation therapy, the emergence of therapeutic resistance has become one of the main hurdles to PC management, and efforts have been made to develop novel molecules that inhibit the activity of persistent AR pathways. The aim of this work is to use a comprehensive in silico virtual screening approach to identify and assess phthalimide derivatives as potential inhibitors of the mutated androgen receptor protein (PDB ID: 1GS4). To find drug-like molecules, the initial library of 1508 phthalimide derivatives was retrieved from the PubChem database and structurally filtered using Lipinski's Rule of Five and an e-pharmacophore hypothesis phase module (Schrodinger) to remove non-drug-like molecules, resulting in 54 molecules. Using the high-throughput, extra-precision molecular docking and Molecular Mechanics-Generalized Born Surface Area free energy calculations, 13 compounds with binding affinities better than the clinical standard (Bicalutamide) were identified. Of these, 5-(1,3-dioxoisoindol-4-yl)-pentanenitrile was selected as the initial lead owing to its ADMET and excellent electronic properties, as determined by DFT calculations. The lead structure was then optimized to address toxicological issues associated with the CN and CO groups, yielding six new structural analogues of the lead compound. The best thermodynamic stability and binding were observed for Lead Analog A (4-heptyl-3-methoxyisoindolin-1-one), with a docking score of −10.742 kcal/mol. Critical pharmacokinetic profiling and toxicity studies demonstrated that this next-generation derivative not only has a greatly diminished risk of hepatotoxicity and mutagenic potential, but also exhibits high membrane permeability and blood-brain barrier penetration. Altogether, these computational results support a synergy between the optimized phthalimide scaffold and its observed potency, revealing a viable targeted therapeutic for prostate cancer that can overcome resistance.