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bioRxiv · 10.1101/2022.08.22.504824

Targeting Plasmodium falciparum calcium dependent protein kinase-1: Computational modelling approach towards the discovery of antimalarial drug from medicinal herbs and clinically approved anti-malarial drugs pharmacophores

Oladipo, E. K.·Adelusi, T. I.·Ojo, T. O.·Quadri, B. O.·Oyewole, P. M.
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Abstract

The Key participants in the calcium signaling process in the malaria parasite are calcium dependent protein kinases. It has been established that Plasmodium falciparum calcium dependent protein kinase 1 (PfCDPK1) is essential for the invasion of host erythrocytes as well as for the parasites asexual development. Due to malarias resistance to currently available anti-malarial medications, it has become necessary to create effective inhibitory agents that target invasion-dependent proteins. In this study, libraries of 856 chemicals were screened using a variety of computational methods. Physicochemical property testing, molecular docking analysis, and pharmacokinetic ADMET profiling were used to determine these drugs capacity to inhibit PfCDPK1. 88 of the 856 compounds derived from known antimalarial botanicals and clinically approved antimalarial drug pharmacophores have demonstrated a potent inhibitory effect on PfCDPK1. Additionally, based on research done on the purported inhibitory standard of PfCDPK1 (Purfalcamine), which had a binding affinity of -8.8 KJ/mol, twelve compounds, which include 17-hydroxyazadiradione, Nimbaflavone, Dehydrocarpaine-II, Picracin, Epicatechin gallate, and Naringin, ZINC000012504271, ZINCC000100029905, ZINC000004149268, ZINC000078832372, ZINC000102739374 and ZINC000198562314 had exhibited better binding affinities (-8.8, -8.8, -9.2, -9.1, -9.3, -10.0, -8.1, -7.9, -7.9, -8.2, -8.3, -7.9 KJ/mol respectively), pharmacokinectics, and physicochemical properties. According to our findings, 88 compounds are likely pharmacological targets with domiciled PfCDPK1 inhibitory effects. Nevertheless, our findings highlight these twelve stand-out compounds, suggesting that they may be the best candidates with regard to therapeutic efficacy.

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Oladipo, E. K., Adelusi, T. I., Ojo, T. O., Quadri, B. O., Oyewole, P. M.. 2022-08-23. Targeting Plasmodium falciparum calcium dependent protein kinase-1: Computational modelling approach towards the discovery of antimalarial drug from medicinal herbs and clinically approved anti-malarial drugs pharmacophores. https://doi.org/10.1101/2022.08.22.504824

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