Drug Lead Compounds For The Discovery Of New Strategies

Recent development in identifying lead molecules for drug discovery includes virtual screening or in silico screening approaches and antibody-structure-based design of pharmacological agents. Virtual screening technique has been established to narrow down the size of screening compound libraries to the most promising drug candidates with high success rates. Antibodies can provide a structural internal image of a given antigen, peptidemimetics derived from complementarity determing region (CDR) loop can be designed as a base on these well-studied antigen combining sites. In the present study, receptor-based virtual screening against BCR-ABL was performed to identify the novel small molecule inhibitor and a small constrained peptidemimetic derived from antl-Pgp antibody was developed to mimic similar biological activity of intact IgG.1. Identification of Small Molecule Inhibitors of BCR/ABL Tyrosine Kinase through Structure Based Virtual ScreeningOver 90% of cases of chronic myelogenous leukemia (CML) and 10% to 25% of cases of adult acute lymphoblastic leukemia (ALL) are associated with a reciprocal translocation between chromosomes 9 and 22 that produces a Bcr-Abl fusion gene. Since transformation by BCR/ABL is absolutely dependent on tyrosine kinase activity, it has been evident that BCR/ABL tyrosine kinase domain could be an attractive target for drug development. Herein, we describe the discovery of novel classes of small molecule inhibitors targeted at the catalytic domains of Abl tyrosine kinase, in which a centrally located "activation loop" is not phosphorylated, by computational 3-D database search. A preliminary DOCK screening against the distinctive inactive conformation of the catalytic domain of BCR/ABL was performed on a smaller 3D database that 291,352 commercially available organic compounds had been built...