Rama K. Kondru

New peroxylactones from the Jamaican sponge Plakinastrella onkodes, with inhibitory activity against the AIDS opportunistic parasitic infection Toxoplasma gondii

Abstract An analysis of the chemical constituents of Plakinastrella onkodes collected in Jamaica yielded three cyclic peroxides, including the known plakortolide (1) and two new analogs of 1. The absolute configuration of plakortolide G ((3R,4R,6R,8S)-3) was determined by ab initio optical rotation computations using a coupled Hartree–Fock (CHF) method implemented in CADPAC. Plakortolide (1) (J. Org. Chem. 1980, 45, 3396) and plakortolide G (3) exhibited potent inhibitory activity against the protozoan Toxoplasma gondii in HFF cells and represent the first marine natural products reported with T. gondii inhibitory activity.

Determination of the absolute configuration of 1,3,5,7-tetramethyl-1,3-dihydroindol-2-one by optical rotation computation

The absolute configuration of 1,3,5,7-tetramethyl-1,3-dihydroindol-2-one was determined by quantum chemical calculations of specific rotation angles with coupled–perturbed Hartree–Fock methods. The computation used molecular geometries obtained from ab initio calculations as well as from molecular mechanics and semi-empirical optimization. In addition to the dependence on geometry optimization strategies, the basis set dependence of the computed rotation angle was examined.

Hepatitis C virus NS5B polymerase: QM/MM calculations show the important role of the internal energy in ligand binding.

The inter- and intramolecular interactions that determine the experimentally observed binding mode of the ligand (2Z)-2-(benzoylamino)-3-[4-(2-bromophenoxy)phenyl]-2-propenoate in complex with hepatitis C virus NS5B polymerase have been studied using QM/MM calculations. DFT-based QM/MM optimizations were performed on a number of ligand conformers in the protein-ligand complex. Using these initial poses, our aim is 2-fold. First, we identify the minimum energy pose. Second, we dissect the energetic contributions to this pose using QM/MM methods. The study reveals the critical importance of internal energy for the proper energy ranking of the docked poses. Using this protocol, we successfully identified three poses that have low RMSD with respect to the crystallographic structure from among the top 20 initially docked poses. We show that the most important energetic component contributing to binding for this particular protein-ligand system is the conformational (i.e., QM internal) energy.