Yunierkis Perez-Castillo, Aliuska Morales Helguera, M.Natalia D. S. Cordeiro, Eduardo Tejera, Cesar Paz-y-Mino, Aminael Sanchez-Rodriguez, Fernanda Borges* and Maykel Cruz-Monteagudo Pages 1107 - 1116 ( 10 )
Background: Virtual methodologies have become essential components of the drug discovery pipeline. Specifically, structure-based drug design methodologies exploit the 3D structure of molecular targets to discover new drug candidates through molecular docking. Recently, dual target ligands of the Adenosine A2A Receptor and Monoamine Oxidase B enzyme have been proposed as effective therapies for the treatment of Parkinson's disease.
Methods: In this paper we propose a structure-based methodology, which is extensively validated, for the discovery of dual Adenosine A2A Receptor/Monoamine Oxidase B ligands. This methodology involves molecular docking studies against both receptors and the evaluation of different scoring functions fusion strategies for maximizing the initial virtual screening enrichment of known dual ligands.
Results: The developed methodology provides high values of enrichment of known ligands, which outperform that of the individual scoring functions. At the same time, the obtained ensemble can be translated in a sequence of steps that should be followed to maximize the enrichment of dual target Adenosine A2A Receptor antagonists and Monoamine Oxidase B inhibitors.
Conclusion: Information relative to docking scores to both targets have to be combined for achieving high dual ligands enrichment. Combining the rankings derived from different scoring functions proved to be a valuable strategy for improving the enrichment relative to single scoring function in virtual screening experiments.
Parkinson's disease, dual target ligands, molecular docking, scoring fusion.
Departamento de Quimica. Universidad Tecnica Particular de Loja. Loja, Molecular Simulation and Drug Design Group, Centro de Bioactivos Quimicos (CBQ), Universidad Central “Marta Abreu” de Las Villas, Santa Clara, 54830, REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Instituto de Investigaciones Biomedicas (IIB), Universidad de Las Americas, 170513 Quito, Instituto de Investigaciones Biomedicas (IIB), Universidad de Las Americas, 170513 Quito, Departamento de Ciencias Naturales, Universidad Tecnica Particular de Loja, Calle París S/N, EC1101608 Loja, CIQUP/Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, Porto 4169-007, Instituto de Investigaciones Biomedicas (IIB), Universidad de Las Americas, 170513 Quito