Abstract
BackgroundQuantitative structure-activity relationships (QSAR) is a technique that is used to produce a model that connects biological activities of compounds to their chemical structures, and molecular docking is a technique that reveals the binding mode and interactions between a drug and its target enzyme. These techniques have been successfully applied in the design and development of many drug candidates and herein were employed to build a model that could help in the development of more potent antimalaria drugs.ResultsDescriptors of the compounds were calculated using the PaDEL-Descriptor software, and Genetic Function Algorithm (GFA) was used to select descriptors and build the model. A robust and reliable model was generated and validated to have internal and external squared correlation coefficient (R2) of 0.9622 and 0.8191, respectively, adjusted squared correlation coefficient (Radj) of 0.9471, and leave-one-out (LOO) cross-validation coefficient (Q2cv) of 0.9223. The model revealed that the antiplasmodial activities of 1,2,4,5-tetraoxane-8-aminoquinoline hybrids depend on MATS3m, GATS8p, GATS8i, and RDF50s descriptors. MATS3m, GATS8i, and RDF50s influenced the antiplasmodial activities of the compounds positively while GATS8p negatively with the greatest influence. The docking result shows strong interactions between 1,2,4,5-tetraoxane-8-aminoquinoline hybrids and Plasmodium falciparum lactate dehydrogenase (pfLDH) with binding affinities ranging from − 6.3 to − 10.9 kcal/mol which were better than that of chloroquine (− 6.1 kcal/mol), suggesting that these compounds could be better inhibitors of pfLDH than chloroquine.ConclusionThe results of this study could serve as a model for designing new potent 1,2,4,5-tetraoxane-8-aminoquinolines with better antiplasmodial activities for the development of highly active antimalaria drugs.
Highlights
Quantitative structure-activity relationships (QSAR) is a technique that is used to produce a model that connects biological activities of compounds to their chemical structures, and molecular docking is a technique that reveals the binding mode and interactions between a drug and its target enzyme
3 Results Genetic function algorithm (GFA) of the material studio software was used to build four QSAR models to study how the chemical structure of 1,2,4,5-tetraoxane-8-aminoquinoline hybrids relates with their biological activities as potent antimalaria
RDF50s indicated the existence of a linear relationship between the antiplasmodial activities of 1, 2,4,5-tetraoxane-8-aminoquinoline hybrids and the 3D molecular distribution of the relative inductive effect of atoms or group of atoms in the molecules calculated at the radius of 5.0 Å from the geometrical centers of each hybrids molecule
Summary
Quantitative structure-activity relationships (QSAR) is a technique that is used to produce a model that connects biological activities of compounds to their chemical structures, and molecular docking is a technique that reveals the binding mode and interactions between a drug and its target enzyme. Malaria accounts for most of the deaths in the world especially in children and pregnant women This infection affected about 219 million persons in 2017 where 92% of this number was from WHO African countries [1]. Since 2005, the World Health Organization recommended the use of artemisinin-based combination therapies (ACTs) for the treatment of P. falciparum malaria [7, 8]. These chemotherapies show excellent efficacy especially in the African region. Resistance to ACTs has been observed and reported to be of an increase in Southeast Asia and its spread to other regions is seriously challenging [10,11,12], the need for a promising antimalarial drugs
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