Determination of the biological activity of complexes formed with PT(II) and 2-pyrimidinethiol using QSAR method based on quantum chemistry

In the study, the subject of drug design was handled with theoretical and computerized chemistry calculations. Ligand-based and structure-based drug development methods were chosen as the main topic in this study. From studies on the A2780 human ovarian cancer gene, 154 platinum-based complexes were selected from the literature for ligand-based drug design. As a result of the calculations, HCTH407P was chosen as the DFT method to be used in geometric optimizations, and the basis set was ZORA relativistic full electron. Approximately 1400 descriptors were calculated taken from NMR, quantum mechanics, and PaDEL. Models were created for all groups using the multiple linear regression (MLR) method from the quantitative structure-activity relationship (QSAR) calculations together with the calculated descriptors. These models were validated with the four principles of the OECD and applied to 30 new drug candidate compounds formed together with platinum and the known biologically active 2-pyrimidinethiol ligand. As a result, 11 compounds were found to have low cytotoxicity and were identified as potential drug candidates. In structure-based drug development, the interactions of metal-containing molecules with DNA, which is one of the ultimate targets in cancer, were investigated. Here, the difficulties of integrating metal-containing compounds into this system were overcome. An effective core basis set (ECP), which deactivates core electrons on the metal atom, was used to make the calculations faster. As in ligand-based drug design, OLYP was chosen as the best DFT method, HayWadt for ECP, LanL2TZ for metal basis set, and def2-TZVP for other atoms.Since, DNA groove binding was examined, planar and +2 charged platinum and 2-pyrimidinethiol complexes consisting only of carrier ligands were formed. Molecular docking calculations were made with a total of 84 complexes composed of 21 biologically active functional compounds in 4 different groups with these complexes. The complexes with the best pose were selected from each group. The metal-containing complexes in the best exposures were subjected to 100ns simulations in the aqueous system. As a result of the simulations, the intermolecular interactions and binding affinities in the structures were examined in detail.