Please use this identifier to cite or link to this item: http://localhost:8080/xmlui/handle/123456789/7856
Title: Ligand based-design of potential schistosomiasis inhibitors through QSAR, homology modeling, molecular dynamics, pharmacokinetics, and DFT studies
Authors: Ja’afaru, Saudatu C.
Uzairu, Adamu
Chandra, Anshuman
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Keywords: Glutathione S-transferase
Ligand based drug design
Molecular docking simulations
Schistosoma mansoni
Schistosomiasis
Issue Date: 2024
Publisher: Journal of Taibah University Medical Sciences
Series/Report no.: Original Article;429-446
Abstract: Objectives: Schistosomiasis, a neglected tropical disease, is a leading cause of mortality in affected geographic areas. Currently, because no vaccine for schistosomiasis is available, control measures rely on widespread administration of the drug praziquantel (PZQ). The mass administration of PZQ has prompted concerns regarding the emergence of drug resistance. Therefore, new therapeutic targets and potential compounds are necessary to combat schistosomiasis. Methods: Twenty-four potent derivatives of PZQ were optimized via density functional theory (DFT) at the B3LYP/6-31G* level. Quantitative structureactivity relationship (QSAR) models were generated and statistically validated, and a lead candidate was selected to develop therapeutic options with improved efficacy against schistosomiasis. The biological and binding energies of the designed compounds were evaluated. In addition, molecular dynamics; drug-likeness; absorption, distribution, metabolism, excretion, and toxicity (ADMET); and DFT studies were performed on the newly designed compounds. Results: Five QSAR models were generated, among which model 1 had favorable validation parameters (R2 train: 0.957, R2 adj: 0.941, LOF: 0.101, Q2cv: 0.906, and R2 test: 0.783) and was chosen to identify a lead candidate. Other statistical parameters for the chosen model included variance inflation factor values ranging from 1.242 to 1.678, and a Y-scrambling coefficient (cRp2) of 0.747. Five new compounds were designed with improved predicted activity (ranging from 5.081 to 7.022) surpassing those of both the lead compound and PZQ (predicted pEC50 of 5.545). Molecular dynamics simulation revealed high binding affinity of the proposed compounds toward the target receptor. ADMET and drug-likeness assessments indicated adherence to Lipinski’s rule of five criteria, thereby suggesting pharmacological and oral safety. In addition, DFT analysis indicated resistance to electronic alteration during chemical reactions. Conclusion: The proposed compounds exhibited potential drug characteristics, thus indicating their suitability for further investigation to enhance schistosomiasis treatment options.
URI: http://localhost:8080/xmlui/handle/123456789/7856
ISSN: 1658-3612
Appears in Collections:Vol 19 No 2 (2024)

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