AccScience Publishing / ITPS / Volume 7 / Issue 1 / DOI: 10.36922/itps.0976
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ORIGINAL RESEARCH ARTICLE

Plasmodium falciparum histoaspartic protease inhibitor: Toxicity investigation and docking study of 2-(2-benzoyl-4-methylphenoxy) quinoline-3-carbaldehyde derivatives

Oluwafemi S. Aina1 ,  Luqman A. Adams1 ,  Adebayo J. Bello2 ,  Oluwole B. Familoni1*
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1 Drug Design Research Group, Department of Chemistry, University of Lagos, Lagos State, Nigeria
2 Department of Chemistry and Biology, Redemeer’s University, Osun State, Nigeria
INNOSC Theranostics and Pharmacological Sciences 2024, 7(1), 0976 https://doi.org/10.36922/itps.0976
Submitted: 23 May 2023 | Accepted: 26 July 2023 | Published: 13 September 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Aspartic proteases can hydrolyze peptide bonds, making them potential targets for drug development against malaria parasites. In particular, inhibiting the histoaspartic protease (HAP) can disrupt the growth phase of Plasmodium falciparum and its ability to degrade hemoglobin for protein synthesis. Compound 5, specifically designed as 2-(2-benzoyl-4-methylphenoxy)quinoline-3-carbaldehyde, served as the basis for designing 50 hypothetical compounds (A1-A50). These compounds were subjected to in silico screening to assess their toxicity profiles, pharmacokinetics, bioactivity scores, and theoretical binding affinities, as a part of the drug design protocol. Out of the 50 compounds, nine lead candidates showed no toxicity to human cells. In addition, ten standard reference antimalarial drugs were included in this study for comparison. The highest binding energies were observed for compound A5 (−11.2 kcal/mol) and A31 (−11.3 kcal/mol), surpassing the performance of mefloquine, the best reference drug, which ranked ninth with a binding energy of (−9.6 kcal/mol). Compound A31 did not exhibit the evidence of interaction with either Asp215 or His32, whereas compound A5 displayed π-π stacking interactions with His32. Mefloquine also did not show any interaction with Asp215 or His32. Moreover, compound A5 demonstrated greater hydrophobic interactions at the active site with most binding residues, except for Lys7 in the hydrophobic region. This characteristic suggests that compound A5 may have the ability to adopt a smaller surface area, exhibit increased biological activity, and have reduced interactions with water, which could facilitate slower clearance. Based on the assessment of various drug-likeness parameters, compound A5 (2-(2-benzoyl-4-methylphenoxy)-7-methylquinoline-3-carbaldehyde) is a potential lead candidate for the development of a new antimalarial drug.

Keywords
Malaria
Mefloquine
Binding energy
Drug leads
Oral bioactivity score
Pharmacokinetics
Docking
Funding
University of Lagos Central Research Committee
Nigerian Government TetFund IBR
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Conflict of interest
The authors declare they have no competing interests.
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INNOSC Theranostics and Pharmacological Sciences, Electronic ISSN: 2705-0823 Published by AccScience Publishing
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