Quantum pharmacological studies on antimalarial drugs

Summary Linear models for the relation between electronic structure and antimalarial activity of chloroquine drugs have been investigated, based on CNDO/2 molecular orbital calculations. The results indicate that changes in electron density on the atoms N1, N2, C4, C9, and C10 have the strongest influence on the pharmacological activity, so that these atoms can be assumed to form the main active center of these drugs. Correlations improve, if substitution on the nucleus of chloroquine and side chain variations are treated separately. The models found seem to be a useful tool for designing new drugs within the chloroquine series.

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Quantenchemisch-pharmakologische Untersuchungen von Antimalaria-Wirkstoffen

Zusammenfassung Auf der Basis von CNDO/2-Rechnungen wurden lineare Modelle für die Relation zwischen Elektronenverteilung und der Antimalaria-Aktivität von Chlorochinen untersucht. Es zeigte sich, daß Veränderungen in den Elektronendichten der Atome N1, N2, C4, C9 und C10 den stärksten Einfluß auf die pharmakologische Wirkung haben. Es kann somit angenommen werden, daß diese Atome die hauptsächlich aktiven Zentren der Verbindung sind. Die Korrelation wird verbessert, wenn die Substitution am Chlorochin-Kern und Variationen der Seitenketten separat behandelt werden. Die aufgefundenen Modellvorstellungen sollten ein nützliches Werkzeug zur gezielten Synthese neuer Wirkstoffe innerhalb der Chlorochin-Reihe darstellen.

     

Structure and dynamics of high-spin Ru in aqueous solution: Ab initio QM/MM molecular dynamics simulation

The structural and dynamical properties of high-spin Ru²⁺ in aqueous solution have been theoretically studied using molecular dynamics (MD) simulations. The conventional MD simulation based on pair potentials gives the overestimated average first shell coordination number of 9, whereas the value of 5.9 was observed when the three-body corrected function was included. A combined ab initio quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulation has been performed to take into account the many-body effects on the hydration shell structure of Ru²⁺. The most important region, the first hydration shell, was treated by ab initio quantum mechanics at UHF level using the SBKJC VDZ ECP basis set for Ru²⁺ and the 6-31G^∗ basis sets for water. An exact coordination number of 6 for the first hydration shell was obtained from the QM/MM simulation. The QM/MM simulation predicts the average Ru²⁺–O distance of 2.42 Å for the first hydration shell, whereas the values of 2.34 and 2.46 Å are resulted from the pair potentials without and with the three-body corrected simulations, respectively. Several other structural properties representing position and orientation of the solvate molecules were evaluated for describing the hydration shell structure of the Ru²⁺ ion in dilute aqueous solution. A mean residence time of 7.1 ps was obtained for water ligands residing in the second hydration shell.