2. Academic Validation
  3. Identification of Potential Multitarget Directed Ligands for Alzheimer's Disease by Coupling Virtual Screening and Experimental Validation

Identification of Potential Multitarget Directed Ligands for Alzheimer's Disease by Coupling Virtual Screening and Experimental Validation

  • J Chem Inf Model. 2026 Mar 9;66(5):2900-2917. doi: 10.1021/acs.jcim.5c02202.
Paulina Valenzuela-Hormazábal 1,  Jessica Valero-Rojas 1 2,  Loreto Martínez-González 3 4,  Sandra Ramos-Inza 3,  Victoria Oviedo-Pino 1,  Cristian González-Ortega 5,  Guillermina Hernando 6,  Jhon J López 7,  Cecilia Scorza 8,  Carolina Echeverry 8,  Margarita Gutierrez 9,  Miguel Reyes-Parada 5,  Ana Martínez 3 4,  David Ramírez 1
Affiliations

Affiliations

  • 1 Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad De Concepción, Concepción 3460000, Chile.
  • 2 Facultad de Ciencias Químicas, Universidad de Concepción, Concepción 3460000, Chile.
  • 3 Centro de Investigaciones Biológicas "Margarita Salas"-CSIC, Madrid 28040, Spain.
  • 4 Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, (CIBERNED), Instituto de Salud Carlos III, Madrid 28029, Spain.
  • 5 Centro de Investigación Biomédica y Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago 9170124, Chile.
  • 6 Instituto de Investigaciones Bioquímicas de Bahía Blanca, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Bahía Blanca B8000CPB, Argentina.
  • 7 Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile.
  • 8 Departamento de Neurofarmacología Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay.
  • 9 Instituto de Química de Recursos Naturales, Universidad de Talca, Talca 3460000, Chile.
PMID: 41728859 DOI: 10.1021/acs.jcim.5c02202
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder (NDD) associated with the accumulation of beta-amyloid plaques (βA), oxidative stress, and a decrease in cholinergic activity among Other pathologies. Given the limitations of current treatments, multitarget strategies present a promising alternative. In this study we prioritized six AD-related protein targets: acetylcholinesterase (AChE), Beta-secretase 1 (BACE-1), Cannabinoid Receptor type 2 (CB2), glycogen synthase kinase 3 beta (GSK-3β), Monoamine Oxidase A (MAO-A), and the neuronal acetylcholine receptor subunit alpha-7 (nAChR7). Ligand- and structure-based virtual screening methods were applied to identify potential multitarget directed ligands (MTDLs), reducing an initial database of 14 million compounds to 21 early stage candidate MTDLs, that were tested experimentally against AChE, BACE-1, GSK-3β, MAO-A, nAChR7, and the additional targets BChE and MAO-B; however, CB2 could not be experimentally assessed. Among the tested molecules, PJ17 exhibited a dual-target profile with submicromolar activity against AChE and GSK-3β, while PJ11 showed notable MAO-B inhibition. Molecular dynamics simulations revealed key common interactions between PJ17 and those targets providing insights into its potential for further hit-to-lead optimization. In addition, PJ17 showed a safe profile in cellular primary culture suggesting its use as a template to design multitarget drugs against AD.

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