De Novo Design of New Inhibitor of Mutated Tyrosine-Kinase for the Myeloid Leukemia Treatment

Background: Chronic myelogenous leukemia is associated with hematopoietic stem cells that are manifested primarily with expansion myelopoiesis. It is the first cancer directly associated with a genetic abnormality. Specifically, it is associated to a particular cytogenetic abnormality, known as Philadelphia chromosome (Ph), which results from a fusion between part of the BCR (“breakpoint cluster region”) gene from chromosome 22 and the Abelson (ABL) gene on chromosome 9 and leads to the formation a new gene leukemia-specific, the BCR-ABL. Since 2011, there are several tyrosine-kinase inhibitors in the market. Due to mutations in the tyrosine-kinase domain, these inhibitors are becoming less effective in the leukemia treatment, and then there is a need for new more effective inhibitors. Methods: The aim of this work is to obtain new tyrosine-kinase inhibitors using in silico tools like de novo drug design, docking and absorption, distribution, metabolism and excretion studies. Results: Using the proposed methodology, an initial library of more than 6000 molecules was obtained. This library was then filtered out using the Tanimoto metric to compute the similarity between the molecules using as parameter the 2D linear hashed fingerprint with a 64-bit address space. The resulting library was then used to run docking studies together with the reference market drugs and their ADME (absorption, distribution, metabolism and excretion) properties were determined. Three compounds with better inhibition capacity and better ADME properties that the commercially available not only for the wild form of enzymes under study but also to its mutated forms were obtained. Conclusion: The fragment based drug design method used in this work turns to be a good alternative to create new drugs that can control this neoplasm. Based on the calculated GScore, the de novo designed molecules have better inhibitor capacity than the tyrosine-kinase inhibitors most used in the market. These molecules shown strong potential to become drugs capable to inhibit all mutations, mainly the T315I mutation, now the leading cause of deaths due to the difficulty of inhibitors to control it.