Developing potential drugs for insomnia through computational analysis

Abstract

Introduction: Insomnia is a condition that affects the quality of life of an individual. It is associated with a lack of sleep or interrupted sleep. If not managed, insomnia may end up causing conditions such as obesity, heart conditions, hypertension, and mental disorders. Lack of sleep is also associated with an increased risk of Alzheimer’s disease. There is, therefore, a need to develop a drug that manages insomnia with desirable clinical outcomes Methods: The canonical smiles of Zolpidem, Suvorexant, Ramelteon, and Triazolam were obtained from PubChem. The study used the online tool SwissSimilarity to identify structural analogs for Zolpidem, Suvorexant, Ramelteon, and Triazolam. The canonical smiles were copied to PubChem Sketcher were converted to a 2- dimensional (2D) format. The Avogadro was used to optimize the ligands. The respective receptors were obtained from the Protein Data Bank. Chimera was used to prepare the receptor and the docking, using AutoDock Vina. SwissADME and Protox server was used in the determination of the pharmacokinetics and toxicity profiles, respectively. Results: Docking scores, pharmacokinetics, and toxicity profiles of the analogs were recorded. Nine structural analogs from the ZINC database (ZINC000004222622, ZINC000003981996, ZINC000003825731, ZINC000000000903, ZINC000039247014, ZINC000010152022, ZINC000000347721, ZINC000065743121 ZINC000022054496) were found to have a better docking score, blood brain barrier permeability, Lipinski’s violations, synthesizability index, gastrointestinal tract absorption, p-glycoprotein substrate metabolism LD50 compared to the parent drug molecules. All the nine molecules had good synthesizability index, gastrointestinal absorption and zero Lipinski violations indicating good oral availability. Conclusions: Ramelteon analogs ZINC000004222622, ZINC000003981996, and ZINC000003825731, Triazolam drug-like molecules, ZINC000000000903, ZINC000039247014, ZINC000010152022, and ZINC000000347721 and Zolpidem drug-like molecules ZINC000065743121 and ZINC000022054496 were identified as the best compound bases on the pharmacokinetic binding to the respective receptors and toxicity profiles.