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Indian Journal of Cancer, Vol. 46, No. 4, October-December, 2009, pp. 335-336 Brief Report Analysis of binding energy activity of imatinib and Abl tyrosine kinase domain based on simple consideration for conformational change: An explanation for variation in imatinib effect in mutated type Wiwanitkit V Wiwanitkit House, Bangkhae, Bangkok 10160 Code Number: cn09077 PMID: 19749465 Abstract Imatinib is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition on the transforming growth factor beta and platelet-derived growth factor pathways. The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat chronic myelogenous leukemia. However, conformational analysis shows that the effect of the drug depends on the potential energy, which varies due to the alpha rotatable angles of the Abl tyrosine kinase domain. In this study, the author determines the change of binding energy between the Abl tyrosine kinase domain, due to the variation in rotatable angles, and bond lengthening. According to this study, the ratio between the required binding energy between the wild and mutated types is equal to 1: 1.16.Keywords: Angle, conformation, imatinib Introduction With the beginning of the new millennium, a new and exciting era for cancer therapy has begun, with the appearance of molecular targeted drugs. [1] Some molecular targeting drugs, such as, Glivec (Imatinib, STI571), have shown amazing effects when compared to the currently used chemotherapy drugs. [1] Chronic myeloid leukemia (CML) is a clonal stem cell disorder, which causes many new cases annually. Research on molecular-targeted therapy confirms that specific protein kinases have broad consequences for the development of future drugs to treat CML. [2] Imatinib is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition on the transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) pathways. [3] Imatinib also creates activity against abl, c-kit, and is approved for the treatment of CML and gastrointestinal stromal tumors. [4] Currently, there are several ongoing studies assessing the efficacy of this novel drug in the therapy of brain tumors, neuroblastomas, and lung and prostate cancer. [5] The improper activation of Abl tyrosine kinase results in CML. [6] The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. [6] However, the conformational analysis shows that the effect of the drug depends on the potential energy which varies due to the alpha rotatable angles of the Abl tyrosine kinase domain. In this study, the author determines the change of binding energy between Abl tyrosine kinase domain, due to the variation in rotatable angles, and bond lengthening. Materials and Methods Basic concepts in binding between imatinib and the Abl tyrosine kinase domain: As previously mentioned, binding between the active side chain of imatinib and the Abl tyrosine kinase domain is the main interaction. The alpha angle is variable and beta is fixed. The wild type of interaction is alpha Glu (0 degree) in, with length = 3.1 angstrom, while the mutated type is alpha out (180 degree), with length = 1.8 angstrom. [7] Quantum chemical analysis for binding energy: This is a calculation-based study. The method is the same as previously described in a recent published work by Wiwanitkit. [8] Basically, each chemical reaction possesses its specific required reaction energy. The primary assumption in this study is that the required reaction energy for the pharmacological reaction between imatinib and the Abl tyrosine kinase domain is equal to A kCal / mol when it occurs within a horizontal angle (wild type). In this study, the theoretical simulation for variation from a 0 to 180 degree change, to derive the mutate type, was performed. The variation of the interaction length from 3.1 to 1.8 was also performed. Calculation for the energy in each binding scenario was done based on the physical theory of force. Results The change in binding energy corresponding to the variation of rotatable angle and interaction length is presented in [Table - 1]. The ratio between the required binding energy between the wild and mutated types is equal to 1: 1.16. Discussion The development of tyrosine phosphorylation inhibitors has transformed the approach to cancer therapy and will probably affect other fields of medicine as well. [9] An interesting point to be clarified in the mechanism of imatinib is the interaction with c-Src. [10] Imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the PDGF receptor. [10] However, imatinib is less effective against c-Src, which is difficult to understand. [10] Within Abl, a mutated typed is also reported. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that may facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. [7] Conformational analysis can be useful to understand the difference within the wild and mutated Abl. Here, the author has found that change in the rotatable angle and interaction length critically affects the binding energy. An increase in the required energy can be observed. This implies the difficulties for occurrence of the reaction and further implies drug resistance. This result confirms the work of Seelinger et al. , which states that the free energy balance between different inactive states is the key to imatinib binding. [10] Proper modifications to imatinib may enhance their binding, and hence, potentially, their therapeutic efficacy. The explanation that some derivatives are highly active while the others are not is fairly good. Also, it reveals the fact that the same drug is effective sometimes and not all the time. References
Copyright 2009 - Indian Journal of Cancer The following images related to this document are available:Photo images[cn09077t1.jpg] |
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