Structure-Based Design of Potential Anti-schistosomiasis Agent Targeting SmHDAC8: An In Silico Approach Utilizing QSAR, MD Simulation and ADMET Prediction

• Published in: Chemistry Africa Vol. 7; no. 2; pp. 725 - 745
• Main Authors: Ja’afaru, Saudatu Chinade, Uzairu, Adamu, Sallau, Muhammed Sani, Ndukwe, George Iloegbulam, Ibrahim, Muhammad Tukur, Danazumi, Ammar Usman
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2024
• Subjects: Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Inorganic Chemistry; Organometallic Chemistry; Original Article; Molecular dynamics; Quantitative structure-activity relationship (QSAR); Schistosoma mansoni histone deacetylase 8 (SmHDAC8); Multiple linear regression genetic function algorithm; Structure based drug design
• ISSN: 2522-5758; 2522-5766
• DOI: 10.1007/s42250-023-00777-2

Due to the increasing emergences of drug resistance, there is a need to discover new drugs that can target Schistosoma mansoni histone deacetylase 8 (SmHDAC8) and effectively combat Schistosomiasis. In view of this, an in-silico approach was employed to identify potential inhibitors by evaluating the binding energy and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of SmHDAC8 inhibitors. Employing density functional theory (DFT) calculations with the B3LYP/6-311G* as basis set, the optimal configuration of SmHDAC8 inhibitors was established, and a quantitative structure activity relationship (QSAR) model was constructed utilizing a combined genetic function approximation and multilinear regression (GFA-MLR) methodology. The selected model demonstrated strong statistical parameters, including R 2 of 0.896, R adj 2 of 0.877, Q cv 2 of 0.863, R test 2 of 0.662, and cR p 2 of 0.747, confirming its reliability. Molecular docking screening was then utilized to position the derivatives into the active site of the SmHDAC8 target (PDB ID: 4BZ8). This analysis revealed Compound 26 as a highly promising lead candidate, displaying a MolDock score of − 137.103 kcal/mol. Four novel compounds were designed, showing improved binding affinities (− 151.376 to − 154.777 kcal/mol) and predicted activities (6.928 – 7.060) compared to the lead compound and standard drug, PZQ. Further validation was conducted through molecular dynamics (MD) simulations on compound 26d , confirming the stability and integrity of the docked complex. Additionally, an assessment of drug-likeness and ADMET properties indicated favorable pharmacokinetic profiles for the designed analogs, with no violations of Lipinski's rule of five. These newly designed derivatives hold promise as novel agents for the treatment of Schistosomiasis.