Machine Learning Neuroprotective Strategy Reveals a Unique Set of Parkinson Therapeutic Nicotine Analogs

Felipe Rojas-Rodríguez1, *, Carlos Morantes2, Andrés Pinzón3, George E. Barreto4, Ricardo Cabezas1, Leonardo Mariño-Ramírez5, Janneth González1
1 Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana. Bogotá D.C, Republic of Colombia
2 Departamento de Biología, Universidad Nacional de Colombia. Bogotá, Republic of Colombia
3 Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Republic of Colombia
4 Department of Biological Sciences, University of Limerick, Limerick, Ireland
5 National Center for Biotechnology Information, National Library of Medicine, National Institute of Health, 8600 Rockville Pike, Bethesda, MD 20894, USA

© 2020 Rojas-Rodríguez et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: ( This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to the author at the Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana. Bogotá D.C, Republic of Colombia; E-mail:



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.


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.


Develop an interdisciplinary computational strategy predicting the neuroprotective activity of a series of 8 novel nicotine analogs over Parkinson's disease.


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.


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.


Hereby, we present a robust novel strategy to assess the neuroprotective potential of biomolecules based on SP architecture. Our theoretical strategy can be further applied to the study new treatments related with SP deregulation and may ultimately offer new opportunities for therapeutic interventions in neurodegenerative diseases.

Keywords: Parkinson’s disease, Nicotine analogs, PI3K/AKT, Machine learning, Artificial Neural Networks, Substanita Nigra.