Rational Design of Potential Bcr-Abl Tyrosine Kinase Inhibitors by the Methods of Molecular Modeling
Anrdrianov A.M.1, Kornoushenko Yu.V.1, Karpenko A.D.2, Bosko I.P.2, Ignatovich Zh.V.3, Koroleva E.V.3
1Institute of Bioorganic Chemistry, NAS of Belarus, Minsk, Republic of Belarus
2United Institute of Informatics Problem, NAS of Belarus, Minsk, Republic of Belarus
3Institute of Chemistry of New Materials, NAS of Belarus, Minsk, Republic of Belarus
Abstract. Discovery of the nature of inhibiting cancer processes by small organic molecules has changed the principles of the development of drug compounds for antitumor therapy. Recent achievements in this area are associated with the design of small-molecule protein kinase inhibitors, organic compounds exhibiting directed pathogenetic action. In this study, in silico design of 38 potential anti-cancer compounds with multikinase profile was carried out based on the derivatives of 2-arylaminopyrimidine. Evaluation of inhibitory activity potential of these compounds against the native and mutant (T315I) forms of Bcr-Abl tyrosine kinase, an enzyme that plays a key role in the pathogenesis of chronic myeloid leukemia characterized by uncontrolled growth myeloid cells in peripheral blood and bone marrow, was performed using molecular modeling tools. As a result, 5 top-ranking compounds that exhibit, according to the calculated data, a high-affinity binding to the native and mutant Bcr-Abl tyrosine kinase were identified. The designed compounds were shown to form good scaffolds for the development of novel potent antitumor drugs.
Key words: protein kinases, Bcr-Abl tyrosine kinase, Bcr-Abl tyrosine kinase inhibitors, computer-aided drug design, pharmacophore-based modeling, molecular docking, quantum chemistry, molecular dynamics.