Browsing by Author "Muller, Ronel"
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- ItemExploring the antimalarial mechanism of action: Adsorption of diverse inhibitors to crystalline malaria pigment (haemozoin).(Stellenbosch : Stellenbosch University, 2017-03) Muller, Ronel; De Villiers, Katherine A.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: The crystallization of free haem (ferriprotoporphyrin IX) into haemozoin within the parasitic food vacuole is a vital detoxification process in the life cycle of the malaria parasite. Quinoline antimalarial drugs achieve their mechanism of action by adsorbing onto the fastest growing face of haemozoin, which brings about inhibition of further crystal growth. Therefore, an in-depth study of the adsorption of quinoline antimalarial drugs and structurally related non-quinoline compounds to β-haematin (synthetic haemozoin) was undertaken in order to assess this hypothesis. Adsorption of clinically-relevant quinoline drugs onto both the fastest and the second fastest growth faces of β-haematin was evaluated using molecular mechanics simulations. The adsorption geometries obtained were consistent with those previously reported in literature. When applying a multiple correlation that takes into account both the percentage speciation at pH 4.8 (pH in the food vacuole), as well as the adsorption onto both the fastest growing crystal faces, a significant linear correlation was found when comparing the calculated adsorption energies (Eads (kcal.mol-1)) and the determined β-haematin growth inhibition activities (Lipid BHIC50), where an R2 value of 0.78 and a P value of 0.004 are found. This observation greatly supported the above mentioned hypothesis. The study was further extended to evaluate the adsorption of a set of non-quinoline compounds onto the two fastest growing crystal faces. A new adsorption geometry was observed where the inhibitors were able to adsorb over two adjacent unit cells, thereby forming π-π interactions to two neighbouring porphyrin structures. This is the first time that this adsorption geometry has been observed. Therefore, following the successful synthesis of a small set of quinoline inhibitors, it was demonstrated that an improved adsorption and a subsequent enhanced β-haematin growth inhibition activity is dependent on the formation of a larger number of intermolecular interactions between the inhibitor and the crystal surface. Finally, by combining all compounds investigated (25 in total) and thereby evaluating a more comprehensive data set, an exponential relationship is found when comparing the calculated adsorption energy (Eads (kcal.mol-1)) and the determined β-haematin growth inhibition activity (NP40 BHIC50), when applying the multiple correlation equation, and upon considering both the percentage speciation at pH 4.8 as well as the adsorption onto both the fastest growing crystal faces. An R2 value of 0.73 with a P value of <0.0001 are obtained. These results add merit to the argument that antimalarial drugs adsorb onto β-haematin to inhibit further crystal growth. Moreover, by determining the necessary intermolecular interactions required for improved adsorption onto these crystal faces, this information could be applied in future drug development to rationally design novel and more active antimalarial drugs.
- ItemThe rational design and synthesis of novel HIV non-nucleoside reverse transcriptase inhibitors(Stellenbosch : Stellenbosch University, 2013-12) Muller, Ronel; Pelly, Stephen C.; Van Otterlo, Willem A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: With a cure for HIV and AIDS still absent, non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a major role in the current antiretroviral treatments used, which have shown to improve and prolong the lives of HIV patients significantly. However, with rapid mutations of the HI virus, the use of these drugs is becoming limited, thereby highlighting the need for the development of new NNRTIs. Previous work by our research team has led to the development of a cyclopropyl-containing indole-based compound with an inhibition activity (IC50 value) of 0.1 μM, as determined in an in vitro single-cycle, non-replicative phenotypic assay. Therefore, in this project, we focussed on enhancing the intermolecular interactions of our compound to three major areas in the NNRTI binding pocket, namely the Tyr181, the Val179, and the Lys101 binding pockets. Hereby we were able to obtain both improved and lower potencies, with our most active compound having an inhibition activity (IC50 value) of 1 nM. For the interaction to the Tyr181 binding pocket, we were thus unable to synthesise a heterocyclic ring system onto our molecule as opposed to the previously used phenyl ring. Secondly, for the interaction to the Lys101 binding pocket we were able to synthesise a tetrazole ring system and an amide functionality onto the 2-position of the indole. Lastly, in our quest to synthesise the cyclopropyl moiety onto our compound for the interaction in the Val179 binding pocket, we were able to investigate the full inhibition effect of this interaction by synthesising a similar compound with no interaction in this binding pocket. Moreover, we were able to synthesise a new compound with a methoxy moiety for this interaction with an inhibition activity (IC50 value) of 1 nM. With this compound only being submitted for efficacy evaluation as a racemic compound mixture, this opened a new door for research possibilities for our team.