Novel PDE5 Inhibitors as a Therapeutic Tool Against Alzheimer's Disease

As a co-investigator (subcontract) of the proposed project, I will be responsible for the computational design part of the grant. Specifically, my research lab will perform the structurebased computational design of the desirable novel PDE5 inhibitors described in the proposal. The initial round of computational design will be based on our recently accomplished computational studies of phosphodiesterases (PDEs) and their substrates/inhibitors [1-6]. Based on the computational design, we will suggest the corresponding chemical synthesis at Columbia University, followed by the inhibitory activity assays for the synthesized compounds. The actual outcome of the wet experimental tests will be used to refine the computational design protocol and improve the rational basis for subsequent predictions. We believe that such an iterative, coupled computational-experimental effort will eventually result in discovery of the desirable, novel PDE5 inhibitors as a therapeutic tool against Alzheimer's disease. The similar computational design approach has been used in my lab for computational design of high-activity mutants of human butyrylcholinesterase (BChE) as a novel anti-cocaine medication, leading to discovery of a set of BChE mutants with a considerably improved catalytic efficiency against the widely abused cocaine [7,8].