XP-951

We present mol. docking and 3-D QSAR studies on a series of tetrahydropyrimid-2-one HIV-1 protease inhibitors whose binding affinities to the enzyme span nearly 6 orders of magnitude.The docking investigations have been carried out with Surflex (GEOM, GEOMX) and Glide (SP and XP) methodologies available through Tripos and Schrodinger suite of tools in the context of Sybyl-X and Maestro interfaces, resp.The alignments for 3-D QSAR studies were obtained by using the automated Surflex-SIM methodol. in Sybyl-X and the analyses were performed using the CoMFA and CoMSIA methods.Addnl., the top-ranked poses obtained from various docking protocols were also employed to generate CoMFA and CoMSIA models to evaluate the qual. consistency of the docked models with exptl. data.Our studies demonstrate that while there are a number of common features in the docked models obtained from Surflex-dock and Glide methodologies, the former sets of models are generally better correlated with deduced exptl. binding modes based on the X-ray structures of known HIV-1 protease complexes with cyclic ureas.The urea moiety common to all the ligands are much more tightly aligned in Surflex docked structures than in the models obtained from Glide SP and XP dockings.The 3-D QSAR models are qual. and quant. similar to those previously reported, suggesting the utility of automatically generated alignments from Surflex-SIM methodol.