Molecular Structure Optimization and Molecular Dynamics Using Hamiltonian Algorithm: Structure of Benzodiazepine Minor Tranquilizers—Towards Non-Empirical Drug Design—

Abstract

Abstract We have studied the molecular dynamics of the benzodiazepine and thienodiazepine minor tranquilizers using a Hamiltonian Algorithm (HA) combined with ab initio molecular orbital methods. The HA utilizes classical dynamics for optimization of the complicated systems. We show that the HA gives an effective search of the potential energy surfaces and we can find an energy minimum even if we start from another energy local minimum. The conformers of these minor tranquilizers are calculated after computation of the molecular dynamics. Relations between electronic states and strength of tranquilizers are studied for about 17 species of benzodiazepines and thienodiazepines which are sold in the Japanese market as minor tranquilizers. The orbital energy levels of the next highest occupied molecular orbital (next-HOMO or HOMO−1) are found to be strongly related to the strength of the tranquilizers. The simple structure–activity relationship is obtained by considering just one-electron properties, i.e., the molecular orbital energies.