This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Many receptor-specific ligand candidates predicted in silico fail to demonstrate their calculated affinity and specificity after synthesis and testing. We hypothesize that docking of three-dimensional (3D) projections of potential target binding agents with 3D projections of macromolecular disease targets visualized on a computer with touch and feel feedback will enable identification of optimal agent designs, and culling of suboptimal agent designs, prior to synthesis. The use of haptic feedback and quantitative measurements of obstacles encountered along the kinetic pathway will enable culling of unfavorable designs, allowing us to synthesize more sensitive and specific molecular probes to support the projection of 3D gene product images of patients superimposed on 3D anatomical images of patients. We will test this hypothesis by synthesizing a genetic probe carrying a newly designed ligand and measuring its actual affinity for the target receptors on human pancreatic cancer cells. Using our account on Salk, we have run EGF-EGFR kinetic binding MD simulations that required 48 hr to converge. The results agreed with bench observations that EGF20-31 failed to bind, while EGF32-48 bound and internalized. Now we wish to carry out larger calculations of additional EGF fragments binding to EGFR with explicit water, which will require more nodes to complete in a reasonable period.
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