Development of an alternative mehod to calculate core electron binding energies (CEBEs) of molecules, and evaluation of its applicability in drug design

Abstract

This project consist of, first, development of a new and efficient technique for calculation of core electron binding energies (CEBEs) of molecules, and, second, investigation of applicability of CEBEs in the field of medicinal chemistry, especially in the study of QSAR(Quantitative Structure-Activity Relationships) that is used in rational drag design. The first stage of the project is considered as basic research, and the second stage as applied research.In the first step in the first stage (Basic research), we want to develop a new and efficient technique for calculation of accurate core electron binding energies (CEBEs) of molecules. CEBEs can be determined experimentally, and they have been useful in the area such as analytical chemistry, polymers and solid-state sciences. Accurate calculation of CEBEs have been possible only recently due to development of density functional theory (DFT). We use DFT theory to calculate accurate CEBEs using different approaches. Initially we test as many different DFT approaches as possible calculating CEBEs of only small isolated molecules (diatomic and polyatomic molecules) that consists of only second law atoms (H, C, N, O, F). We use a computer program called ADF (Amsterdam Density Functional). In the second step, we want to develop a reliable and efficient technique of calculation of CEBEs of molecules, in gas state, that contain the third low atoms (Si, P, S, and C1). In the third step of the basic research, we want to develop a technique to calculate CEBEs of solid state and molecules adsorbed/chemisorbed surface of solid. Treatment of molecules in solid state and crystals must be quite different from isolated molecule in gas state. We also plan to carry out a comparative study between a semiempirical HAM/3 (Hydrogenic Atoms in Molecules, version 3) method with nonempirical DFT. The author of HAM/3 described that it is a semiemprical version of DFT. Through the comparative study, we want to find out numerically whether HAM/3 is really a semiempirical version of DFT by calculating ionization energies of molecules.ln the stage "Applied Research" of the project, we investigate, first, applicability of CEBE as descriptor in SAR ( structure-activity relationships") and QSAR (Quantitative Structure-Activity Relationship). CEBE shift is proportional to Hammett sigma (o) constant, which is an important descriptor in SAR/QSAR. We expect CEBE shift (and CEBE) can be also important descriptor. We first test this possibility with series of phenols that show toxicity against fast growing cells. Biological activity of the series is known. We repeat the similar test to another series of compounds, such as phenoxyacetic acids that have function as plant growth regulator. We use pattern recognition techniques for SAR and linear multiple regression for QSAR studies. If we can confirm that CEBEs can be useful descriptors in SAR/QSAR for the two representative series, we apply the same techniques for the remaining four series of compounds that have different biological activity. They are, neolignans, active against leishmania donovani; polycyclic aromatic hydrocarbons that have carcinogenic activity; antispermatogenic hexahydroindenopyridines; and thiosemicarbazones, active against leishmania donovani . lnvestigations of SAR/QSAR of the series of the neolignans using other types of descriptors than CEBEs have been done in collaboration with Professor L. E. S. Barata of Chemistry Department of UNICAMP and Professor B. Rossi-Bergamann of Carlos Chagas Filho Biophysics lnstitute/ UFRJ. A comparative study between the previous results with the present will be done. Study of mode of interaction between a drug (ligand) and its receptor is fundamental importance in order to understand the origin of its biological activity. Crystal structure of piruvato kinase of Leishmania mexicanais available in Brookhaven Protein Data Bank. We study the mode of interaction between neolignans and the protein... (AU)