Identification of Potent ABL Inhibitors from Coumestrol: An Integrative In Silico Approach

Abstract

Chronic Myeloid Leukemia (CML) is known as clonal myeloproliferative disorder resulted by the proliferative and deregulated expression of the BCR-ABL gene. Although targeting the BCR-ABL gene is an effective treatment for CML, the development of drug intolerance and drug resistance is still an issue for BCR-ABL targeted therapy. With an aim to develop novel BCR-ABL inhibitors with fewer side effects, we started with the anti-cancerous natural compound coumestrol as the lead. Chalcone and pyrazole are the well-exploited scaffolds in the anticancer domain; hence, in this work, we designed novel coumestrol derivatives with these structures. In order to quantify the structural changes, we employed in silico methods. The new drug leads were compared with the FDA-approved CML drug bosutinib. The molecular orbital analysis of the selected lead compounds was assessed by Density Functional Theory (DFT) approach. Molecular Dynamic (MD) computations were performed on the most promising leads to find the stability. Following which, the pharmacokinetics parameters of the screened compounds were also analyzed to check the drug-like property.