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EVALUATION OF THE INHIBITORY EFFECT OF A CANNABIDIOL DERIVATIVE AGAINST THE PLASMODIUM FALCIPARUM DIHYDROFOLATE REDUCTASE

Parker Elijah Joshua, Ugochi Olivia Njoku, Zikora Kizito Anyaegbunam, Joseph Chinedum Ndefo, Amaechi Lydia Ogara, Samuel Cosmas*, Olanrewaju Ayodeji Durojaye*

Abstract: Introduction:The alarming rate of drug failure against malaria necessitates the development and deployment of novel and highly efficacious antimalarial drugs. The use of natural plant remedies in curtailing the malaria catastrophe remains uncertain, as only a small fraction of plants has been evaluated and developed for their medicinal potentials. However, many communities in malaria-affected regions still rely on natural plants and herbs, despite documented concerns about efficacy and adverse effects. One plant of continuous controversy is Cannabis sativa, known mainly for its psychoactive effects but possesses other activities. Cannabidiol, an isolated constituent of cannabis has been reported to possess moderate antimalarial activity in vitro. Materials and Methods: The Autodock Vina software was used in carrying out a molecular docking study on cycloguanil, cannabidiol and its C2H5 analogue against the Plasmodium falciparum dihydrofolate reductase. The physiochemical analysis, lipophilicity, solubility, pharmacokinetics and Lipinski drug likeness of these molecules were also evaluated through extensive structure-activity relationship study. Results: The free binding energies of cycloguanil, cannabidiol and its modified analogue were -8.0, -8.9 and -8.9Kcal/mol respectively. The low binding score (more negative value) exhibited by cannabidiol and its C2H5 analogue shows they are respectively the better antimalarial agents. The inability of the C2H5 analogue of cannabidiol to cross the blood brain barrier as displayed in the structure-activity relationship results shows it poses no threat to normal brain function which makes it the most ideal antimalarial agent against the P. falciparum DHFR. All the experimental ligands exhibited high gastrointestinal absorption rates and are also moderately soluble in water. Conclusion: The results showed that the C2H5 analogue of gedunin might be the most ideal antimalarial agent haven exhibited a low binding score and no interference with the CNS through BBB permeation. The laboratory synthesis and preclinical study on this compound is therefore recommended in order to confirm itsantimalarial potentials. Keywords:Docking; Cannabidiol; Plasmodium falciparum; Blood Brain Barrier; Dihydrofolate reductase.

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