IN-SILICO IDENTIFICATION AND SCREENING OF NOVEL DORA TO PREVENT SD DECREASING THE RISK FOR NDDS

Abstract

Aim: Insomnia, a cause for sleep deprivation (SD) could result in comorbidities like neurodegenerative diseases (NDDs), as sleep plays an important role in removal of neurotoxic peptides via various mechanisms. Current pharmaceutical therapies are confined to sedation only, instead of considering the whole molecular interlinking pathways that can prevent NDDs and adverse effects also. This research is done to discover a novel drug (DORA) addressing the molecular pathways of sleep recovery and neuroprotection both utilizing the orexin receptors in the brain and enhancing circadian expression and synaptic plasticity. Dual Orexin Receptor Antagonist (DORA) medications are used to maintain sleep and hence stimulate neurowaste clearance mechanism. A synergistic approach combining Artificial Intelligence and Machine Learning (AIML) with computational biology is utilized here, where using a Deep Learning-based predictive model, a list of 12 blood brain barrier (BBB) permeable compounds is extracted from PubChem with 90% similarity to pre-existing DORA (Lemborexant) taking as reference, which all were docked to the Orexin receptors (OxR1 and OxR2) using Swiss Dock, compounds with highest binding affinity were visualized for ligand-protein interactions using BOVIA Discovery Studio Visualizer, ensuring high-precision structural validation. Finally, pharmacokinetics analysis was done by SwissADME to check the efficacy of the drug. Such an AIML integrated approach of drug discovery saves time and cost of wet lab experiments. Furthermore, the drug discovered should be validated for probable action in vivo. Result: This AI-augmented pipeline identified a novel DORA, (1R,2R)-2-cyclohexa-2,4-dien-1 yl-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-N-pyridin-2-ylcyclopropane-1-carboxamide, having an exceptional binding energy with both the orexin receptors involved in sleep-wake regulation and neuroinflammation, hence serves bidirectionally to treat insomnia along with prevention from NDDs. Conclusion: A novel DORA is found to treat SD, Insomnia, and, in turn, to prevent associated comorbidities and NDDs like PD, ALS, HD or AD. This discovery of novel DORA is done through an in-silico approach, which utilizes AI and a variety of machine learning based techniques and computational algorithms. This method saves a great deal of time, capital, and labor, making it incredibly cost-effective for drug discovery and development; however, the identified new drug can show different activities within the body. Therefore, we advise validating our in-silico findings using in vivo experiments.