A geometry optimization and molecular electrostatic potential mapping study of structure-activity relationship for some anti-Alzheimer agents

Molecular geometries of some substituted (pyrroloamino)pyridines which poss ess anti-Alzheimer activity were optimized and potential-derived CHelpG poi nt charges were computed using ab initio SCF molecular orbital approach emp loying the 3-21G basis set. AMI molecular orbital calculations were perform ed using these optimized geometries and thus optimized Hybridization Displa cement Charges (HDC) combined with Lowdin charges continuously distributed in three dimension were obtained. Molecular electrostatic potential (MEP) m aps of the molecules were obtained in two ways: (i) using the HDC-based mod el with the help of which MEP minima near the molecules were located, and ( ii) using the CHelpG point charges, MEP values on the van der Waals surface s of the molecules were computed. The MEP maps computed using both the meth ods have negative MEP regions near the pyridine nitrogen atom which appears to be the main binding site of the molecules with the appropriate receptor . Both electrostatic interaction and lipophilic association between these m olecules and the receptor appear to contribute to biological activity.