Structure-Based Drug Design in Discovering Target Specific Drugs against Plasmodium falciparum Adenylosuccinate Lyase
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Date
2021-05-03
Journal Title
Journal ISSN
Volume Title
Publisher
Tropical Journal of Natural Product Research
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, structurebased 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
Description
Keywords
Malaria, Drug design, Antimalarial activity, Molecular docking, Drug target, ADMET properties, Ezekiel Adebiyi, Nigeria, ACE: Applied Informatics and Communication, Digital Development, Covenant University