Pharmacokinetics and drug-likeness of anticancer phytoconstituents: ADMET, Molecular docking, and Simulation studies

Abstract

Breast cancer (BC) is the most commonly diagnosed cancer in women around the world. Several genetic mutations tend to induce the risk of BC progression. SPDEF (Sam pointed domain containing ETS transcription factor) is a prostate-derived ETS factor that maintains homeostasis, differentiation of epithelial tissues, and heritable alterations in cancer. Plant secondary metabolites like flavonoids, terpenoids, and alkaloids have shown anticarcinogenic effect in several literatures. Therefore, in this study the SPDEF protein was used as potential breast cancer therapeutic target. Pharmacokinetic properties (ADMET), drug-likeness, and molecular docking of the fifteen phytoconstituents were assessed against SPDEF protein by various in silico approaches. The results showed that genistein, 2-hydroxychalcone, ajoene, and allicin had no toxicity. As per toxicological endpoints prediction study, the median lethal dosage (LD50) values vary from 159 to 3919 mg/Kg. All of the phytoconstituents derivatives taken into account in this investigation, are projected to be good candidates for P-glycoprotein (p-gp). Using in silico methods, the fifteen phytoconstituents identified from the different plants were predicted for their inhibitory actions against SPDEF protein, suggesting their breast cancer therapeutic potential. Silibinin, codonolactone and genistein have showed the lowest binding energy (-7.7, -6.1 and -6.1 kcal/mol) respectively and predicted to have the best inhibitory effect against SPDEF protein. We selected these three phytoconstituents for molecular dynamic simulation at 200 ns. In a comparison analysis, the Silibinin-receptor complex structure qualifies for the maximum parameters. The predictions about the pharmacokinetic properties of these phytoconstituents would form the basis for future in vivo, and in vitro experiments to identify the most appropriate therapeutic compound.