U. Chandra Singh

Ab initio calculations on the structure and nature of the hydrogen bonded complex H2S ⋅⋅⋅ HF

Ab initio calculations employing an extended basis set and correlation energy estimates at the MP2 (second order Moller–Plesset) level have been used to estimate the binding energy, minimum energy S ...F distance, and minimum energy bisector angle θ (angle between the twofold axis of H2S and the S ...F line) for the hydrogen bonded complex H2S ... HF. The calculated distance and bisector angle θ are in reasonable agreement with experiment; the calculated binding energy can be used to provide a good estimate of the (as yet unknown) experimental value. Morokuma component analyses and simple electrostatic (molecular mechanics) calculations have been carried out on the complex as a function of bisector angle and they demonstrated that, despite suggestions to the contrary, the H2S ... HF bisector angle is predominantly determined by the electrostatic energy.

Modeling complex molecular interactions involving proteins and DNA.

We have presented a perspective of progress in three areas of simulations of complex molecules: the development of force fields for molecular simulation; the application of computer graphics, molecular mechanics and molecular dynamics in simulations of DNA and DNA-drug complexes and the application of computer graphics, molecular mechanics and quantum mechanics in studies of enzyme substrate interactions. It is our perspective that improvements are being made in force fields, and these will allow a more accurate simulation of structures and energies of complex molecules. In the area of DNA molecular mechanics and dynamics, it is clear that the use of computer graphics model building combined with NMR NOE data is a potentially very powerful tool in accurately determining structures of drug-DNA complexes using molecular mechanics and dynamics. Finally, we are in a position to reasonably simulate structures and (qualitatively) energies for complete reaction pathways of enzymes using a combination of computer graphics, molecular mechanics and quantum mechanics. More accurate energies and pathways are sure to follow, using the combined molecular mechanics/quantum mechanics optimization developed by Singh and the free energy perturbation methods pioneered in Groningen and Houston.

Structural changes by sulfoxidation of phenothiazine drugs

SummaryThe side-chain conformations of psychoactive phenothiazine drugs in crystals are different from those of biologically inactive ring sulfoxide metabolites. This study examines the potential energies, molecular conformations and electrostatic potentials in chlorpromazine, levomepromazine (methotrimeprazine), their sulfoxide metabolites and methoxypromazine. The purpose of the study was to examine the significance of the different crystal conformations of active and inactive phenothiazine derivatives, and to determine why phenothiazine drugs lose most of their biological activity by sulfoxidation. Quantum mechanics and molecular mechanics calculations demonstrated that conformations with the side chain folded over the ring structure had lowest potential energy in vacuo, both in the drugs and in the sulfoxide metabolites. In the sulfoxides, side chain conformations corresponding to the crystal structure of chlorpromazine sulfoxide were characterized by stronger negative electrostatic potentials around the ring system than in the parent drugs. This may weaken the electrostatic interaction of sulfoxide metabolites with negatively charged domains in dopamine receptors, and cause the sulfoxides to be virtually inactive in dopamine receptor binding and related pharmacological tests.