Implementation of docking, molecular dynamics and free energy to investigate drug potency of novel BCR-ABLT315I inhibitors as an alternative to ponatinib

Abstract

Today, a significant proportion of health costs is dedicated to cancer diagnosis and treatment. Despite considerable advances made in cancer research, the treatment of this disease is still facing numerous challenges. One of the main problems in this field is drug resistance, which in most cases, incidence of mutations in the target molecules is responsible for not responding to prescribed treatments. Chronic myeloid leukemia (CML), is a cancer that is not exempt to this rule. It has been shown that BCR-ABL plays a central role in the emergence of CML and targeting this molecule is a part of all the related therapies. Some mutations in BCR-ABL protein such as T315I reduces the effectiveness of drugs in patients. Compounds such as PBA2, CD-200 and JNJ-26854165 have been introduced as novel candidates for CML treatment in different in vitro/in vivo studies and show potential inhibitory impacts on BCR-ABLT315I. In the present study, our group utilizes computational analysis to investigated interactions and compare the efficiency of designed small molecules to inhibit the BCR-ABLT315I functional domain. Results obtained during docking, analysis of hydrogen bonds and free energy calculation indicated that JNJ-26854165 is a more suitable agent to BCR-ABLT315I inhibition than the other two candidates. However, ponatinib (control agent) shows a higher BCR-ABLT315I inhibitory potency than JNJ-26854165 in the present investigation. Our study demonstrates that none of the three candidate drugs is as potent as ponatinib in terms of targeting the mutant BCR-ABLT315I. © 2021 Elsevier B.V.