Antimalarial drug discovery against malaria parasites through haplopine modification: An advanced computational approach

Shopnil Akash; Guendouzi Abdelkrim; Imren Bayil; Md Eram Hosen; Nobendu Mukerjee; Abdullah F Shater; Fayez M Saleh; Ghadeer M Albadrani; Muath Q Al-Ghadi; Mohamed M Abdel-Daim; Tuğba Taşkin Tok

doi:10.1111/jcmm.17940

Antimalarial drug discovery against malaria parasites through haplopine modification: An advanced computational approach

J Cell Mol Med. 2023 Oct;27(20):3168-3188. doi: 10.1111/jcmm.17940. Epub 2023 Sep 19.

Authors

Affiliations

¹ Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International, University, Dhaka, Bangladesh.
² Laboratory of Chemistry, Synthesis, Properties and Applications. (LCSPA), University of Saida, Saïda, Algeria.
³ Department of Bioinformatics and computational biology, Gaziantep University, Gaziantep, Turkey.
⁴ Professor Joarder DNA and Chromosome Research Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, Bangladesh.
⁵ Department of Microbiology, West Bengal State University, Kolkata, India.
⁶ Department of Health Sciences, Novel Global Community Educational Foundation, Hebersham, Australia.
⁷ Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.
⁸ Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia.
⁹ Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
¹⁰ Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.
¹¹ Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia.
¹² Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt.

Abstract

The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by Plasmodium spp., which includes Apicoplast DNA polymerase and Plasmodium falciparum cysteine protease falcipain-2. These components play a critical role in their life cycle and metabolic pathway, and are involved in the breakdown of erythrocyte hemoglobin in the host, making them promising targets for anti-malarial drug design. Our current study has been designed to explore the potential inhibitors from haplopine derivatives against these two targets using an in silico approach. A total of nine haplopine derivatives were used to perform molecular docking, and the results revealed that Ligands 03 and 05 showed strong binding affinity compared to the control compound atovaquone. Furthermore, these ligand-protein complexes underwent molecular dynamics simulations, and the results demonstrated that the complexes maintained strong stability in terms of RMSD (root mean square deviation), RMSF (root mean square fluctuation), and Rg (radius of gyration) over a 100 ns simulation period. Additionally, PCA (principal component analysis) analysis and the dynamic cross-correlation matrix showed positive outcomes for the protein-ligand complexes. Moreover, the compounds exhibited no violations of the Lipinski rule, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions yielded positive results without indicating any toxicity. Finally, density functional theory (DFT) and molecular electrostatic potential calculations were conducted, revealing that the mentioned derivatives exhibited better stability and outstanding performance. Overall, this computational approach suggests that these haplopine derivatives could serve as a potential source for developing new, effective antimalarial drugs to combat malaria. However, further in vitro or in vivo studies might be conducted to determine their actual effectiveness.

Keywords: pathogenesis; ADMET; Apicoplast DNA polymerase; DFT; malaria; molecular docking.