In a systematic effort to design potent inhibitors of the anti-apoptotic tyrosine kinase BTK (Bruton�s tyrosine kinase) as anti-leukemic agents with apoptosis-promoting and chemosensitizing properties, we have constructed a three-dimensional homology model of the BTK kinase domain. Our modeling studies revealed a distinct rectangular binding pocket near the hinge region of the BTK kinase domain with Leu 460, Tyr 476, Arg 525, and Asp 539 residues occupying the corners of the rectangle. The dimensions of this rectangle are approximately 18 � 8 � 9 � 17 Å, and the thickness of the pocket is approximately 7 Å. Advanced docking procedures were employed for the rational design of leflunomide metabolite (LFM) analogs with a high likelihood to bind favorably to the catalytic site within the kinase domai
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