Machine learning neuroprotective strategy reveals a unique set of Parkinson therapeutic nicotine analogs

peer-reviewed
Aims: Present a novel machine learning computational strategy to predict the neuroprotection potential of nicotine analogs acting over the behavior of unpaired signaling pathways in Parkinson's disease. Background: Dopaminergic replacement has been used for Parkinson’s Disease (PD) treatment with positive effects on motor symptomatology but low progression and prevention effects. Epidemiological studies have shown that nicotine consumption decreases PD prevalence through neuroprotective mechanisms activation associated with the overstimulation of signaling pathways (SP) such as PI3K/AKT through nicotinic acetylcholine receptors (e.g α7 nAChRs) and over-expression of anti-apoptotic genes such as Bcl-2. Nicotine analogs with similar neuroprotective activity but decreased secondary effects remains as promissory field. Objective: Develop an interdisciplinary computational strategy predicting the neuroprotective activity of a series of 8 novel nicotine analogs over Parkinson's disease. Methods: We present a computational strategy integrating structural bioinformatics, SP manual reconstruction, and deep learning to predict the potential neuroprotective activity of 8 novel nicotine analogs over the behavior of PI3K/AKT. We performed a protein-ligand analysis between nicotine analogs and α7 nAChRs receptor using geometrical conformers, physicochemical characterization of the analogs and developed a manually curated neuroprotective datasets to analyze their potential activity. Additionally, we developed a predictive machine-learning model for neuroprotection in PD through the integration of Markov Chain Monte-Carlo transition matrix for the 2 SP with synthetic training datasets of the physicochemical properties and structural dataset. Results: Our model was able to predict the potential neuroprotective activity of seven new nicotine analogs based on the binomial Bcl-2 response regulated by the activation of PI3K/AKT. Conclusion: Hereby, we present a robust novel strategy to