A SHAPE-BASED AND CHEMISTRY-BASED DOCKING METHOD AND ITS USE IN THE DESIGN OF HIV-1 PROTEASE INHIBITORS

The program DOCK [1,2] has been used successfully to identify molecule s which will bind to a specified receptor [3]. The original method ran ks molecules based on their shape complementarity to the receptor site and relies on the chemist to bring the appropriate electrostatic or h ydrogen bond properties into the molecular skeletons obtained in the s earch. This is useful when screening a small database of compounds, wh ere it is not likely that molecules with both the correct shape and el ectrostatic properties will be found. As large databases are more like ly to have redundant molecular shapes with a variety of functionality (e.g., members of a congeneric series), it would be useful to have a m ethod which identities molecules with both the correct shape and funct ionality. To this end we have modified the DOCK 1.0 method to target u ser-specified atom types to selected positions in the receptor site. T he target sites can be chosen based on structural evidence, calculatio n or inspection. Targeted-DOCK improves the ability of the DOCK method to find the crystallographically determined binding mode of a ligand. Additionally, targeted-DOCK searches a database of small molecules at 100-1000 times the rate of DOCK 1.0, allowing more molecules to be sc reened and more sophisticated scoring schemes to be employed. Targeted -DOCK has been used successfully in the design of a novel non-peptide inhibitor of HIV-1 protease.