Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach

Luciane B Silva; Elenilze F B Ferreira; Maryam; José M Espejo-Román; Glauber V Costa; Josiane V Cruz; Njogu M Kimani; Josivan S Costa; José A H M Bittencourt; Jorddy N Cruz; Joaquín M Campos; Cleydson B R Santos

doi:10.3390/molecules28031035

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach

Molecules. 2023 Jan 19;28(3):1035. doi: 10.3390/molecules28031035.

Authors

Affiliations

¹ Graduate Program in Medicinal Chemistry and Molecular Modeling, Health Science Institute, Federal University of Pará, Belém 66075-110, Brazil.
² Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, Brazil.
³ Laboratory of Organic Chemistry and Biochemistry, University of the State of Amapá, Macapá 68900-070, Brazil.
⁴ COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad 45550, Pakistan.
⁵ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, Spain.
⁶ Laboratory of Biotechnology in Natural Products, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, Brazil.
⁷ Department of Physical Sciences, University of Embu, Embu P.O. Box 6-60100, Kenya.

Abstract

Acetylcholinesterase (AChE) enzymes play an essential role in the development of Alzheimer's disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the hAChE B site of the human acetylcholinesterase (hAChE) enzyme employed in this investigation, which was obtained from the Protein Data Bank (PDB ID 4EY6), allowed for the prediction of the binding affinity and free binding energy between the protein and the ligand. Virtual screening was performed to obtain structures similar to Galantamine (GNT) with potential hAChE activity. The top 200 hit compounds were prioritized through the use of filters in ZincPharmer, with special features related to the pharmacophore. Critical analyses were carried out, such as hierarchical clustering analysis (HCA), ADME/Tox predictions, molecular docking, molecular simulation studies, synthetic accessibility (SA), lipophilicity, water solubility, and hot spots to confirm the stable binding of the two promising molecules (ZINC16951574-LMQC2, and ZINC08342556-LMQC5). The metabolism prediction, with metabolites M3-2, which is formed by Glutathionation reaction (Phase II), M1-2, and M2-2 formed from the reaction of S-oxidation and Aliphatic hydroxylation (Phase I), were both reactive but with no side effects. Theoretical synthetic routes and prediction of synthetic accessibility for the most promising compounds are also proposed. In conclusion, this study shows that in silico modeling can be used to create new drug candidate inhibitors for hAChE. The compounds ZINC16951574-LMQC2, and ZINC08342556-LMQC5 are particularly promising for oral administration because they have a favorable drug-likeness profile, excellent lipid solubility, high bioavailability, and adequate pharmacokinetics.

Keywords: ADME; Alzheimer’s disease; molecular docking and molecular dynamics.

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease* / drug therapy
Cholinesterase Inhibitors* / chemistry
Enzyme Inhibitors / therapeutic use
Galantamine / pharmacology
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation

Substances

Cholinesterase Inhibitors
Galantamine
Acetylcholinesterase
Enzyme Inhibitors

Grants and funding

The authors gratefully acknowledge the financial support provided from PROPESP/UFPA. Computational support of the Laboratory of Modeling and Computational Chemistry (LMQC) linked to the Department of Biological Sciences at Federal University of Amapá (UNIFAP/Macapá-Brazil), to the Graduate Program in Medicinal Chemistry and Molecular Modeling, Health Science Institute at Federal University of Pará (UFPA/Belém-Brazil), University of the State of Amapá (UEAP) and Department of Pharmaceutical and Organic Chemistry—Institute of Biosanitary Research ibs.GRANADA—University of Granada (UGR-Granada-Spain).