MM3(96) parameterization for camptothecin analogs: an ab initio and molecular mechanics study.

Torsional parameters for MM3(96) were derived for the missing atom types present in the natural product camptothecin (CPT). Potential energy curves were calculated via ab initio calculations on representative compounds for dihedral angles containing these missing parameters. Gaussian 92 at the restricted Hartree-Fock level of theory using the standard 6-31G** and 4-31G** basis sets, was used for all the quantum-mechanics calculations. Missing MM3 torsional terms were obtained by optimizing the V1, V2 and V3 parameters such that MM3 could reproduce the ab initio torsional profile. MM3 calculated molecular structures that compare well with the ab initio results. Using the newly developed parameters, conformational analyses and QSAR studies of camptothecin analogs were undertaken. MM3 predicts two distinct 'boatlike' conformations for the alpha-hydroxy lactone moiety. The low-energy lactone conformation predicted by MM3 is in general agreement with reported X-ray crystal structures of CPT iodoacetate and 7-ethyl-10-(4-piperidino)piperidinylcarbonyloxy CPT HCl as well as the ab initio structure of a CPT-like alpha-hydroxy lactone.