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.

     

Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors

Binding free energies were calculated for the inhibitors lopinavir, ritonavir, saquinavir, indinavir, amprenavir, and nelfinavir bound to HIV-1 protease. An MMPB/SA-type analysis was applied to conformational samples from 3 ns explicit solvent molecular dynamics simulations of the enzyme-inhibitor complexes. Binding affinities and the sampled conformations of the inhibitor and enzyme were compared between different HIV-1 protease protonation states to find the most likely protonation state of the enzyme in the complex with each of the inhibitors. The resulting set of protonation states leads to good agreement between calculated and experimental binding affinities. Results from the MMPB/SA analysis are compared with an explicit/implicit hybrid scheme and with MMGB/SA methods. It is found that the inclusion of explicit water molecules may offer a slight advantage in reproducing absolute binding free energies while the use of the Generalized Born approximation significantly affects the accuracy of the calculated binding affinities.