Quantum chemical and physicochemical influences on structure–activity relations and drug design
Joyce J. Kaufman · International Journal of Quantum Chemistry · 1979
Abstract Quantum chemical results will be presented on drugs, carcinogens, teratogens, and endogenous biomolecules using our new nonempirical ab initio MODPOT/VRDDO method, which incorporates as options to our ab initio LCAO‐MO‐SCF/CI programs ab initio effective core model potentials (MODPOT) permitting one to calculate only the valence electrons explicitly yet accurately and an integral prescreening technique (VRDDO, variable retention of diatomic differential overlap) especially effective for spatially extended molecules. For molecules of the size of those of interest the MODPOT/VRDDO calculations run an order‐of‐magnitude faster than with our own fast ab initio programs and still retain accuracy to the third decimal place for the valence electron properties. We have also just implemented a new efficient MERGE technique which allows us to reuse integrals from a common skeletal fragment and only to have to recalculate those for a new atom or group or a change in its position. Examples will be presented of the use of this technique on a carcinogenic polycyclic aromatic hydrocarbon and its metabolites. The pKa's, oil‐water partition, and drug distribution coefficients as a sensitive function of pH have been measured for a number of drugs as well as for relevant endogenous biomolecules. The pH dependence of the lipophilicities of such molecules has profound implication on appropriate use of such data in QSAR studies.