Polypharmacological drug design opportunities against Parkinson's disease

Abstract

Background: Parkinson's disease is an attractive disease model to extend research towards a better understanding of the interrelationship between genes and the environment (exposome) therefore is an ideal model for a polypharmacological approach due to its clinical heterogeneity. Methods: In this paper, we present a series of polypharmacological chemical scaffolds extracted from ChEMBL 30 Database, with two or more targets of PD-related proteins obtained through chemoinformatics methods. This way, we describe the first adaptation of the Dual Activity Difference (DAD) map that allows the direct identification of "dual activity cliffs". Results: We identified 25 antiparkinson small molecules whose pharmacological targets are directed to dopaminergic and muscarinic acetyl choline M1-M5 receptors; 2 small molecules with three pharmacological targets with norepinephrine transporter, dopaminergic D1-D2 and muscarinic acetyl choline M1-M5 receptors; 6 with both targets norepinephrine transporter and muscarinic acetyl choline M1-M5 receptors; 2 small molecules with norepinephrine transporter and muscarinic acetyl choline M1-M5 receptors and 1 with both adenosine A2a and Dopamine D1-D5 receptors. Conclusion: Chemoinformatics methods identified 36 polypharmacological chemical scaffolds related to Parkinson's disease. Demonstrating that the design of polypharmacological drugs is an opportunity in PD.