Molecular Dynamic Simulation Study on Chromones and Flavonoids for the In Silico Designing of a Potential Ligand Inhibiting mTOR Pathway in Breast Cancer

Breast cancer is a severe malignancy responsible for significant mortality in women globally. This has attracted a wider attention of the scientific community in order to find an effective therapeutic solution by the development of novel, potent antagonistic bioavailable ligands to be used as future anticancer drugs. Mechanistic target of rapamycin (mTOR), being a protein kinase, has been implicated in variety of activities regulating cell growth, survival, metabolism, and immunity. mTOR activation has been associated with tumor growth and metastasis as well. Since chromones and flavonoids are an important class of natural products having numerous biological properties, the aim of our study was to explore these molecules for the development of a potential bioavailable inhibitor against mTOR using computer-aided drug designing (CADD). Results indicated that the best designed ligand displayed maximum binding affinity (ΔG − 4.91 kcal/mol) around the binding cleft along with lower RMSD value, exhibiting safety and efficacy features as well. Further molecular docking studies based on PEM, equilibrated NVT-NPT, radius of gyration, and RMSF revealed the stability of the complex as well. The substrate recruiting triad of mTOR protein was targeted, for which a library of molecules was developed and after extensive screening, a final ligand molecule (lig34) was identified as the most promising candidate having enough binding energy and fits best with biosafety parameters. Ligand (lig34) was adjudged best upon the bioavailability parameters, displaying inhibitory characteristics with lower toxicity levels.