Structure-Based Drug Design in Discovering Target Specific Drugs against Plasmodium falciparum Adenylosuccinate Lyase doi.org/10.26538/tjnpr/v5i4.23
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Abstract
The emergence of bioinformatics tools and methods has impressively increased the chances of the discovery of new antimalarial drugs that can act through new modes of action, with high efficacy against the deadly Plasmodium falciparum. An essential protein in the salvage of Plasmodium falciparum purines is adenylosuccinate lyase (ADSL), necessary for the synthesis of parasite’s DNA, and therefore can be a potential antimalarial drug target. Hence, structure-based drug design (SBDD) was employed to screen a large dataset of compounds downloaded from the PubChem database against homology modelled Plasmodium falciparum adenylosuccinate lyase (PfADSL). A total of 1,082 compounds were successfully prepared using PyRX software. This was after 3,697 compounds obtained from the similarity evaluation search on 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) were filtered with Lipinski's rule of five (RO5). AutoDock vina software was employed to perform the virtual screening against the biological target using the downloaded ligands from PubChem database with a center grid of x, y, z set on 15.930, 54.398, -5.213 and grid size of x, y, z set on 80,80, 80. A post-screening analysis showed that the five best hits from the screening possessed better binding affinities, within the ranges of -10.9 and -10.5 (kcal/mol), when compared to AICAR (- 8.6 kcal/mol) and chloroquine (-6.0 kcal/mol) standards. The best hits also showed moderate toxicity and good pharmacokinetic properties. Thus, these compounds could be further validated, optimized, synthesized, and transformed into successful commercially-available antimalarial drugs.
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