Abstract
Oral squamous cell carcinoma (OSCC) is a major cause of death in developing countries because of high tobacco consumption. RAC-alpha serine-threonine kinase (AKT1) is considered as an attractive drug target because its prolonged activation and overexpression are associated with cancer progression and metastasis. In addition, several AKT1 inhibitors are being developed to control OSCC and other associated forms of cancers. We performed a screening of the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database to discover promising AKT1 inhibitors which pass through various important filters such as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, physicochemical properties, PAINS (pan-assay interference compounds) filters, PASS (prediction of activity spectra for substances) analysis, and specific interactions with AKT1. Molecules bearing admirable binding affinity and specificity towards AKT1 were selected for further analysis. Initially, we identified 30 natural compounds bearing appreciable affinity and specific interaction with AKT1. Finally, tuberosin and villosol were selected as potent and selective AKT1 inhibitors. To obtain deeper insights into binding mechanism and selectivity, we performed an all-atom molecular dynamics (MD) simulation and principal component analysis (PCA). We observed that both tuberosin and villosol strongly bind to AKT1, and their complexes were stable throughout the simulation trajectories. Our in-depth structure analysis suggested that tuberosin and villosol could be further exploited in the therapeutic targeting of OSCC and other cancers after further clinical validations.