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Antimalarial drug discovery against malaria parasites through haplopine modification: An advanced computational approach |
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| Authors: | 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 |
| Affiliation: | 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 Contribution: Conceptualization (equal), Formal analysis (equal), Investigation (equal), Methodology (equal), Resources (equal), Writing - original draft (equal);3. Department of Bioinformatics and computational biology, Gaziantep University, Gaziantep, Turkey Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Resources (equal), Writing - original draft (equal);4. Professor Joarder DNA and Chromosome Research Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, Bangladesh Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Validation (equal), Visualization (equal), Writing - original draft (equal);5. Department of Microbiology, West Bengal State University, Kolkata, India Department of Health Sciences, Novel Global Community Educational Foundation, Hebersham, Australia Contribution: Formal analysis (equal), Investigation (equal), Methodology (equal), Software (equal), Visualization (equal), Writing - original draft (equal);6. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia Contribution: Investigation (equal), Resources (equal), Software (equal), Supervision (equal), Validation (equal), Visualization (equal), Writing - review & editing (equal);7. Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia Contribution: Formal analysis (equal), Methodology (equal), Resources (equal), Supervision (equal), Validation (equal), Writing - review & editing (equal);8. Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia Contribution: Data curation (equal), Investigation (equal), Software (equal), Supervision (equal), Validation (equal), Visualization (equal);9. Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia Contribution: Software (equal), Supervision (equal), Validation (equal), Writing - review & editing (equal);10. Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt Contribution: Supervision (equal), Validation (equal), Writing - review & editing (equal);11. Department of Bioinformatics and computational biology, Gaziantep University, Gaziantep, Turkey Contribution: Supervision (equal), Validation (equal), Writing - review & editing (equal) |
| 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: | ADMET Apicoplast DNA polymerase DFT malaria molecular docking pathogenesis |