In a previous work we have presented a numerical procedure for the calculation of the internal chemical hardness tensor at the molecular orbital resolution level from standard density functional calculations. In this article we describe an improvement of our method using the thermal extensions of density functional theory. Furthermore, new concepts are introduced in the orbitally resolved theory of chemical reactivity. Traditional molecular orbital theories of chemical reactivity are based only on considerations concerning the highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs) of molecules, supposed to describe the behavior towards electrophiles, respectively, nucleophiles. By applying our methodology to two test molecular systems, namely water and ferrocene, we show how chemical reactivity can be differentiated against hard and soft electrophiles (acids) and hard and soft nucleophiles (bases). As a by-product of the numerical algorithms being used, a self-consistent method for calculating the molecular chemical potential is also described.

QSAR concerning the anti-HIV and cytotoxic activities of a series of HEPT analogues has been established using a Hansch-type approach (TSAR™), a neural network approach (TSAR) and a pharmacophore search method (CATALYST™). The techniques employed allowed reliable activity predictions and confirmed the heterogeneity of this series of compounds, which was previously established in biochemical experiments.

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.

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.