Computational modeling, ligand-based drug design, drug-likeness and ADMET properties studies of series of chromen-2-ones analogues as anti-cancer agents

Abstract

Abstract Background In spite of the significant escalation in the depth of our conception and regulation of breast cancer over the past decades, the malady is still a serious community health challenge globally and poses a substantial tasks. Selective estrogen modulators (SERMs) such as Tamoxifen are approved for the therapy of this illness but developed drug resistance and unwanted side effects such as endometrial cancer caused by the long-term Tamoxifen chemotherapy limit their therapeutic applicability. Hence, developing new ER+ drugs with better therapeutic effect is strongly needed. In an attempt to overcome this challenge, this research is aimed at designing novel chromen-2-one analogues with better inhibition capacity against MCF-7 breast cancer cell line via structural modification of the reference compound and predict their activities using a developed QSAR model. Results Four models were developed, and the first was selected for the design as it has the highest statistical parameters such as: coefficient of determination (R2 = 0.950), cross-validation coefficient (Qcv2 = 0.912), adjusted R2 (Radj2 = 0.935), and external validation R2 (Rpred2 = 0.7485). Twelve (12) new novel chromen-2-one analogs were designed through structural modification of the reference compound. Their activities was predicted using the selected model, and their pIC50 was found to be better than that of the reference compound and standard drug (Tamoxifen) used in the research. Results of pharmacokinetic study of the designed compounds revealed that they possess drug-likeness properties as none of them violated the Lipinski’s rule of five while ADMET studies confirmed designed compounds 6, 8, 11 and 12 as orally safe and non-toxic. Furthermore, molecular docking analysis was performed between these orally safe designed compounds and the active site of the ER+ receptor and the result showed that they have higher binding affinities than the reference compound and the standard drug used for this research. Conclusion Hence, designed compounds 6, 8, 11 and 12 can be used as novel ER+ breast cancer drug candidates after performing in vivo and in vitro studies.