Robert Mcdowell

Fragment-based discovery of nonpeptidic BACE-1 inhibitors using tethering.

BACE-1 (beta-site amyloid precursor protein cleaving enzyme), a prominent target in Alzheimers disease drug discovery efforts, was surveyed using Tethering technology to discover small molecule fragment ligands that bind to the enzyme active site. Screens of a library of >15000 thiol-containing fragments versus a panel of BACE-1 active site cysteine mutants under redox-controlled conditions revealed several novel amine-containing fragments that could be selectively captured by subsets of the tethering sites. For one such hit class, defined by a central aminobenzylpiperidine (ABP) moiety, X-ray crystal structures of BACE mutant-disulfide conjugates revealed that the fragment bound by engaging both catalytic aspartates with hydrogen bonds. The affinities of ABP fragments were improved by structure-guided chemistry, first for conjugation as thiol-containing fragments and then for stand-alone, noncovalent inhibition of wild-type (WT) BACE-1 activity. Crystallography confirmed that the inhibitors bound in exactly the same mode as the disulfide-conjugated fragments that were originally selected from the screen. The ABP ligands represent a new type of nonpeptidic BACE-1 inhibitor motif that has not been described in the aspartyl protease literature and may serve as a starting point for the development of BACE-1-directed Alzheimers disease therapeutics.

Demarcation and integration of gridded data

Abstract Programs for demarking regions of gridded data bounded by local minima and numerically integrating gridded data within a closed boundary are presented. Although the programs were written for electron density analysis, the algorithms are general and can be applied to other problems.

Electron density analysis of the wittig reaction between methylenephosphorane and formaldehyde

Abstract The existence of two oxaphosphetanes in the reaction of methylenephosphorane with formaldehyde is confirmed at the 3-21G* basis-set level. Bonds to phosphorus are generally shorter than when optimized without polarization functions. Projected electron densities are computed and integrated spatial electron populations (ISEP) are obtained for various fragments and compared during the course of reaction.