Identification of repurposed protein kinase B binders from FDA-approved drug library: a hybrid–structure activity relationship and systems modeling based approach

Abstract

Food and Drug Administration (FDA)-approved drugs may be repurposed against those diseases, for which their therapeutic action has not been described. The present study deals with repurposing FDA-approved drugs for selective targeting of protein kinase B (PKB/Akt) for anti-cancer activity, through a two-tier (Cell and Target) model hybridization protocol implemented with support vector machine-based learning method. The hybridization was done as per rules of reaction kinetics. The hybridization process was facilitated as a standalone application for free access at https://github.com/undwivedi/Akt-Selective.git. The selectivity of the ligands for PKB/Akt binding was also evaluated on the basis of mitophagy system model for anti-apoptotic activity. Screening of the FDA-approved drug library, using the developed H- SAR model, led to identification of four compounds (Cas nos. 94749-08-3, 57808-66-9, 62-13-5, 76-43-7), bearing the selectivity for PKB/Akt. Since, the identified compounds have already crossed the barriers of absorption, distribution, metabolism, excretion, toxicity in clinical trials, therefore are safe to be considered for repurposing individually or in combination with other drugs.Communicated by Ramaswamy H. Sarma