Computer-aided discovery of novel SmDHODH inhibitors for schistosomiasis therapy: Ligand-based drug design, molecular docking, molecular dynamic simulations, drug-likeness, and ADMET studies.

Autor: Ja'afaru SC; Department of Chemistry, Ahmadu Bello University, Zaria, Nigeria.; Department of Chemistry, Aliko Dangote University of Science and Technology, Wudil, Nigeria., Uzairu A; Department of Chemistry, Ahmadu Bello University, Zaria, Nigeria., Hossain S; Department of Pharmacy, Jahangirnagar University, Savar, Dhaka, Bangladesh., Ullah MH; Department of Pharmacy, University of Cyberjaya Medical Science, Cyberjaya Selangor, Malaysia., Sallau MS; Department of Chemistry, Ahmadu Bello University, Zaria, Nigeria., Ndukwe GI; Department of Chemistry, Ahmadu Bello University, Zaria, Nigeria., Ibrahim MT; Department of Chemistry, Ahmadu Bello University, Zaria, Nigeria., Bayil I; Department of Bioinformatics and Computational Biology, Gaziantep University, Gaziantep, Turkey., Moin AT; Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chattogram, Bangladesh.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2024 Sep 12; Vol. 18 (9), pp. e0012453. Date of Electronic Publication: 2024 Sep 12 (Print Publication: 2024).
DOI: 10.1371/journal.pntd.0012453
Abstrakt: Schistosomiasis, also known as bilharzia or snail fever, is a tropical parasitic disease resulting from flatworms of the Schistosoma genus. This often overlooked disease has significant impacts in affected regions, causing enduring morbidity, hindering child development, reducing productivity, and creating economic burdens. Praziquantel (PZQ) is currently the only treatment option for schistosomiasis. Given the potential rise of drug resistance and the limited treatment choices available, there is a need to develop more effective inhibitors for this neglected tropical disease (NTD). In view of this, quantitative structure-activity relationship studies (QSAR), molecular docking, molecular dynamics simulations, drug-likeness, and ADMET predictions were applied to 31 inhibitors of Schistosoma mansoni Dihydroorotate dehydrogenase (SmDHODH). The designed QSAR model demonstrated robust statistical parameters including an R2 of 0.911, R2adj of 0.890, Q2cv of 0.686, R2pred of 0.807, and cR2p of 0.825, confirming its robustness. Compound 26, identified as the most active derivative, emerged as a lead candidate for new potential inhibitors through ligand-based drug design. Subsequently, 12 novel compounds (26A-26L) were designed with enhanced inhibition activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding and hydrophobic interactions, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules (26A and 26L). Furthermore, drug-likeness and ADMET prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for treating schistosomiasis.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Ja’afaru et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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