The antimalarial activity of a series of synthetic 1,2,4-trioxanes is correlated with molecular structure by using a pharmacophore search method (CATALYST). The technique is shown to have predictive accuracy and confirms that docking between an active trioxane and the receptor, heme, is the crucial step for drug action.

Ab initio and density functional calculations have been performed on a simple model of the Cope and reverse Cope elimination reactions. The correlational energies have been taken into account up to the MP4(SDQ)/ 6-311G** and CCSD(T)/6-311++G** levels for RHF methods or using different (nonlocal) exchange and correlation functionals for the density functional theory. The calculated activation energies and free energies for both hydrogenated and deuterated reagents were found to be in good agreement with the available experimental data as well as primary kinetic isotope effects. The bond order analysis predicts an almost completely synchronous reaction path for correlated methods and a little advanced H transfer for the HF method. The intrinsic reaction coordinate path following method shows that although the reaction is concerted, the H transfer slightly precedes the C-N bond breaking. Modeling the solvent effect explained the solvent dependence of the Cope (reverse Cope) products equilibrium. Any very significant hydrogen tunneling could be excluded from the shape of the Born-Oppenheimer potential energy surface and from the good agreement between the calculated and measured primary kinetic isotope effects. From these results and the computed minimal energy path, a refined picture of both the Cope and reverse Cope eliminations implying a one-step slightly dissymmetric reaction mechanism could be proposed.

The purpose of the present work was to develop a method allowing one to extract the information needed for the construction of the internal chemical hardness tensor at the molecular orbital level from standard density functional calculations. This method is based on the Janak theorem and on the extension of the Slater transition-state concept. A detailed discussion of the current ideas about the validity of the Janak theorem is presented as well as of the established relations of this subject with the ensemble V-representability problem. The internal chemical hardness tensor has been obtained for water molecule as an example system. Its structure is consistent with the criteria for the internal molecular stability.

Replication of human immunodeficiency virus 1 (HIV-1) uses a viral reverse transcriptase (RT) to convert its positive-strand RNA into double stranded DNA, which is then integrated into host genome. Reverse transcription is a complex event involving p66 and p51 RT subunits but also several viral proteins including Nef, Tat, Vif, IN, NCp7 and p55gag. Viral RNA itself forms a primer/template complex by association with a cellular tRNA(Lys3) which is already present in mature virions. A RT initiation complex (RTIC) is thus formed which may also involve cellular protein upon viral entry. X rays diffraction and NMR studies of free or inhibitor-bound RT have led to the recognition of RT 3D structure, and allowed a thorough understanding of the mode of action of classical competitive nucleoside RT inhibitors (NRTIs) and of the binding of allosteric, non NRTIs (NNRTIs) inhibitors. This also opened an access to computer-aided drug design and modeling. Current NNRTIs represent, in terms of chemical structures, a heterogeneous class of inhibitors currently undergoing extensive development. By contrast with NRTIs, they seem to block initiation steps of reverse transcription. Molecular dynamics, detailed analysis of their interaction with RT as well as the incidence, in the series, of cases of non classical biological behavior, as illustrated here for a new family of compounds, suggest mechanisms of action which are not understandable without considering the involvement of the RTIC as a whole. This opens the exciting perspective of developing new compounds based on this integrated knowledge. Key Words: Nonnucleoside reverse transcriptase inhibitors (NNRTIs); Reverse transcriptase initiation complex (RTIC); Human immunodeficiency virus (HIV); Non classical nonnucleoside reverse transcriptase inhibitors; Molecular modeling; Docking; QSAR; Natural endogenous reverse transcription (NERT).