Recent Patents on Anti-Cancer Drug Discovery, 2009, 4, 000-000 1 1574-8928/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd. Basis for Resistance to Imatinib in 16 BCR-ABL Mutants as Determined Using Molecular Dynamics Tai-Sung Lee 1* , Steven J. Potts 2 and Maher Albitar 3 1 Consortium for Bioinformatics and Computational Biology, and Department of Chemistry, University of Minnesota, Minneapolis, Minnesota; MN 55455, USA, 2 Aperio Technologies, Vista, California; CA 92081, USA, 3 Quest Diagnostics Nichols Institute, San Juan Capistrano, California, CA 92690-6130 USA Received: September 3, 2008; Accepted: December 3, 2008; Revised: December 5, 2008 Abstract: Large-scale (~36,000 atoms) long-time (30 ns each) molecular dynamics (MD) simulations on the complex of imatinib and 16 common mutants of the ABL tyrosine kinase domain have been performed to study the imatinib resistance mechanisms at the atomic level. MD simulations show that long time computational simulations could offer insight information that static models, simple homology modeling methods, or short-time simulations cannot provide for the BCR-ABL imatinib resistance problem. Three possible types of mutational effects from those mutants are found: the direct effect on the contact interaction with imatinib (e.g. some P-loop mutations), the effect on the conformation of a remote region contacting with imatinib (e.g. T315I), and the effect on interaction between two regions within the BCR-ABL domain (e.g. H396P). Insights of possible imatinib resistance mechanisms, not consistent with current consensus, are revealed from various analyses and our findings suggest that drugs with different binding modes may be necessary to overcome the drug resistance due to T315I and other mutations. The relevant patents are discussed. Keywords: BCR-ABL, imatinib resistance, molecular dynamics simulation, MD simulation INTRODUCTION Chronic myelogenous leukemia (CML) is a form of chronic leukemia caused by a characteristic chromosomal translocation called the Philadelphia chromosome [1-5]. CML is triggered by the BCR-ABL oncoprotein containing a constitutively activated BCR-ABL tyrosine kinase domain [6, 7]. Hence inhibitors of BCR-ABL domain have been used successfully to treat most chronic phase CML [8]. Imatinib is an inhibitor of the ABL tyrosine kinase domain and is currently used to treat CML [9-11]. It is currently marketed as Gleevec or Glivec (Europe/Australia). Although imatinib is an effective inhibitor in most cases, mutations of BCR-ABL often show different degrees of resistance to imatinib, especially the T315I mutation and mutations in the ATP phosphate-binding loop (P-loop) [12- 15]. Patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy due to imatinib resistance [12, 16, 17]. The understanding of the mechanism of imatinib resistance clearly is a critical step toward imatinib modification or new inhibitors design [18- 22]. There have been significant amount of analysis done based on the crystal structure of the complex of imatinib and BCR-ABL domain [18, 19, 23-30]. The crystal structure is very valuable information for understanding the molecular basis of the imatinib binding. However, the crystal structure *Address correspondence to this author at the Consortium for Bioinformatics and Computational Biology, and Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, MN 55455, USA; Tel: +1-612-624-1772; Fax: +1-612-626-7541; E-mail: taisung@umn.edu is an average structure and does not necessary represent the true structure, especially in the case that the structure undergoes a rapid equilibrium within few conformations. Furthermore, mutation effect analysis based on the static structure normally ignores possible short or long range conformational changes neither any dynamics effect due to thermal motions is included. Finally, the crystal structure, although potentially close to the true structure in vivo or in vitro, might be significantly different from the true structure in certain regions since the experimental conditions of a crystal structure are very different from the real-life conditions. Computational simulations can provide structure details, energy landscape, dynamics behaviors, and other properties which experiments cannot or have difficulties to offer. Relative few computational simulations have been done on the imatinib resistance problem probably due to the size of the system. Monte Carlo simulations have been reported to study tyrosine kinases binding specificity and drug resistance [31]. Molecular dynamics (MD) simulations [32] and MM- PBSA [33] have been proven useful to study protein-ligand interactions. A 0.4ns MD simulation with cutoff models has been reported [34] and some insights of imatinib resistance due to T315I have been revealed. Such small-scale and/or short-time simulations could provide relatively fast ways to estimate binding free energies or establish simple models to evaluate mutational effects or to help design new drugs. However, small-scale and/or short-time simulations are more valuable only in local regions, and can not account for larger area structural changes common in flexible molecules like kinases. We recently have performed 20ns MD simu-