Antimalarial drug discovery through in silico scaffold hopping using a database of natural products of Kenya

Abstract

Despite the efforts to 'roll back malaria', statistics still shows that there are 97 countries and territories with ongoing malaria transmission, and 7 countries i n the prevention or reintroduction phase, making a total of 104 countries and territories in which malaria is presently considered endemic 4. Globally, an estimated 3.4 billion people are at risk of malaria. WHO estimates that 207 million cases of malaria occurred globally in 2012 and 627 000 deaths were registered. Of the cases (80%) and de aths (90%) occurred in Africa. The multi - drug resistance to the widely recommended and provided drug treatments (Chloroquine and Sulphadoxine - Pyrimethamine) across Asia , South America and Africa has prompted the use of Artemisinin - based combination treatments (ACTS) 1. This necessitates profiling of new antimalarial drugs that have low resistant strains towards P. falciparum. Strategic plans need to be put in place to di scover and develop novel antimalarial compounds that are not encumbered by pre - existing mechanisms of drug resistance to avoid ever - increasing toll of malaria on tropical areas 2 In this research, a computational approach is employed to identify suitable scaffolds form a database of natural products of Kenya (mitishamba.uonbi.ac.ke ) that can be used as alternative antimalarial drugs. Benzoxazine (Cappamensin A based on its similarity to Primaquine), Chromones (Abyssinone V, a promising compound) and Naph thoquinone (Lapachol) have been carefully chosen; with IC50 values of the isolated natural products serving as guiding values. Heavy computational techniques such as Generation of 3 - D molecular database, Virtual Screening, Calculation of probability assign ment curves 3, 2 - D and 3 - D similarity searches have been used to identify the natural products of prime focus. Compounds exhibiting high probability of being active based on the calculations have been synthesized and subjected to in vitro ass ay against PfD HODH enzyme