Pharmacokinetic and pharmacodynamic profiling of compounds similar to paracetamol from zinc database: an in silico analysis

Abstract

Introduction: Paracetamol is the most used drug for the management of pain and as an antipyretic through its mechanism of action on Cox 1,2 and 3 receptors. Paracetamol is a lipid-soluble molecule that can pass through the Blood Brain Barrier. Paracetamol has been formulated differently to ensure the optimal onset and duration of action as both analgesic and as antipyretic. Paracetamol overdose is associated with major side effects such as liver damage through its metabolite N-acetyl-p-benzoquinone Imine. Methods: This study generated zinc compounds that are similar in structure to Paracetamol through Ligand-based virtual screening. Molecular docking of these compounds to Cox 1, 2, and 3 receptors followed through Structure-based virtual screening. Compounds with better docking scores to these receptors were analyzed for pharmacokinetics and toxicity profiles. Results: ZINC01714506; 0.986; ZINC01714507; 0.986; and ZINC00394165; 0.987 showed the highest docking scores to cox 3 receptor with probability scores of -6.7kcal/mol, -6.4 and -6.2 kcal/ mol as compared to Paracetamol with -5.3kcal/mol. ZINC01714507; 0.986; ZINC01714506; 0.986; and ZINC00394165; 0.987; showed higher docking scores to Cox 2 with docking scores of -8.3kcal.mol, -8.1kcal/mole and -8.0 kcal/mol compared to paracetamol with -6.6kcal/mol. ZINC00394165; 0.987; ZINC00406627; 0.980; and ZINC01714506; 0.986; showed highest docking scores to Cox-1 than paracetamol  with scores of -7.7kcal/mol, -7.6 and-7.6kcal/mol. ZINC01714506; 0.986 was predicted the safest with oral LD50 of 2000mg/kg as compared to paracetamol’s 338mg/kg. ZINC00294715; 0.980, ZINC01747085; 0.985, ZINC00394165; 0.987, ZINC00406627; 0.980, ZINC01557001; 0.987 and ZINC19281575; 0.992 were predicted hepatoactive. ZINC00294715; 0.980; ZINC01557001; 0.987; and ZINC19281575; 0.992; lack Blood Brain Barrier permeation. All compounds showed high GIT absorption and all conform to Lipinski’s rule of five. Conclusion: ZINC01557001; 0.987; ZINC01714506; 0.986; ZINC34120167; 0.994; ZINC00394165; 0.987, ZINC01714507; 0.986; and ZINC01747085; 0.985; are promising in drug discovery for new analgesic and antipyretic drugs, based on better docking scores and better oral LD50