Abstract
BackgrondIn silico studies are essential techniques in the modern medicinal chemistry. QSAR modeling and molecular docking are important techniques in both drug discovery and development and have been successfully deployed in the field of medicinal chemistry for the discovery, design, and development of many drug candidates. These techniques were used in this work to come up with a model that relate 2,5-disubstituted furans with their antiplasmodium activities for the development of more active antimalarial drugs.ResultsPredictive and robust QSAR model was generated using Genetic Function Algorithm. The model was statistically validated to have internal and external squared correlation coefficient, R2 of 0.982 and 0.735 respectively; predictive squared correlation coefficient, R2pred of 0.599; adjusted squared correlation coefficient, Radj of 0.974; and leave-one-out cross-validation coefficient, Q2cv of 0.966. It was found out that the antiplasmodium activities of 2,5-disubstituted furans relied on the parameters: GATS5c, minsCl RDF130m, RDF75p, and RDF115s descriptors. All the descriptors except minsCl influenced the antiplasmodium activities of the compounds negatively. That is, their increase decreases the activities of the furans and vice versa. The docking study revealed that most of the furans bind more tightly to Plasmodium falciparum lactate dehydrogenase (pfLDH) than chloroquine, but the enzyme may not be their major target.ConclusionInsight into the relationship between 2,5-disubstituted furans and their antiplasmodium activities has been revealed from the results of this work. Therefore, this could serve as a model for designing novel 2,5-disubstituted furans as potential antimalarial drugs with better activities.
Highlights
World Health Organization reported 228 million cases and 405,000 deaths worldwide from malaria disease in 2018, where children (< 5 years) accounted for 272,000 deaths
World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) as firstline treatment for P. falciparum (Martinelli et al, 2008)
Resistance to ACTs is increasing in South East Asia Region, the Greater Mekong Subregion (GMS), and Western Pacific Region (World Health Organization, 2019)
Summary
World Health Organization reported 228 million cases and 405,000 deaths worldwide from malaria disease in 2018, where children (< 5 years) accounted for 272,000 deaths. This made it one of the most lives threatening disease prevalent in Africa, where 93% and 94% of the 2018 global cases and deaths respectively came from the region (World Health Organization, 2019). Resistance to ACTs is increasing in South East Asia Region, the Greater Mekong Subregion (GMS), and Western Pacific Region (World Health Organization, 2019). This could spread to other regions of the world, the need for highly potent antimalaria with low propensity to resistance
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