Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors. 2021

Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
Facultad de Ciencias, Instituto de Química, Pontificia Universidad Católica de Valparaíso, Av. Universidad #330, Curauma, Valparaíso, Chile. Electronic address: marco.mellado@pucv.cl.

Monoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful implementation was corroborated by studying twenty-three synthetized chalcones (151-173) based on the generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B potent and selective inhibitors, with IC50 against this isoform in the nanomolar range, being (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC50 of 170 nM). Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out. Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was -10.3 Kcal/mol, justifying the MAO-B high selectivity of these compounds. Both theoretical and experimental structure-activity relationship studies were performed, and substitution patterns were established to increase MAO-B selectivity and inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly synthesis and biological evaluations.

UI MeSH Term Description Entries
D008995 Monoamine Oxidase An enzyme that catalyzes the oxidative deamination of naturally occurring monoamines. It is a flavin-containing enzyme that is localized in mitochondrial membranes, whether in nerve terminals, the liver, or other organs. Monoamine oxidase is important in regulating the metabolic degradation of catecholamines and serotonin in neural or target tissues. Hepatic monoamine oxidase has a crucial defensive role in inactivating circulating monoamines or those, such as tyramine, that originate in the gut and are absorbed into the portal circulation. (From Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 8th ed, p415) EC 1.4.3.4. Amine Oxidase (Flavin-Containing),MAO,MAO-A,MAO-B,Monoamine Oxidase A,Monoamine Oxidase B,Type A Monoamine Oxidase,Type B Monoamine Oxidase,Tyramine Oxidase,MAO A,MAO B,Oxidase, Monoamine,Oxidase, Tyramine
D008996 Monoamine Oxidase Inhibitors A chemically heterogeneous group of drugs that have in common the ability to block oxidative deamination of naturally occurring monoamines. (From Gilman, et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p414) MAO Inhibitor,MAO Inhibitors,Reversible Inhibitors of Monoamine Oxidase,Monoamine Oxidase Inhibitor,RIMA (Reversible Inhibitor of Monoamine Oxidase A),Reversible Inhibitor of Monoamine Oxidase,Inhibitor, MAO,Inhibitor, Monoamine Oxidase,Inhibitors, MAO,Inhibitors, Monoamine Oxidase
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D006860 Hydrogen Bonding A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. Hydrogen Bonds,Bond, Hydrogen,Hydrogen Bond
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D013816 Thermodynamics A rigorously mathematical analysis of energy relationships (heat, work, temperature, and equilibrium). It describes systems whose states are determined by thermal parameters, such as temperature, in addition to mechanical and electromagnetic parameters. (From Hawley's Condensed Chemical Dictionary, 12th ed) Thermodynamic
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D047188 Chalcones Derivatives of CHALCONE that are important intermediates in the formation of FLAVONOIDS with anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties. 1,3-Diphenyl-propanediones,1,3-Diphenyl-propenones,1,3-Diphenylpropanediones,1,3-Diphenylpropenones,Chalconoids,1,3 Diphenyl propanediones,1,3 Diphenyl propenones,1,3 Diphenylpropanediones,1,3 Diphenylpropenones
D057927 Hydrophobic and Hydrophilic Interactions The thermodynamic interaction between a substance and WATER. Hydrophilic Interactions,Hydrophilic and Hydrophobic Interactions,Hydrophilicity,Hydrophobic Interactions,Hydrophobicity,Hydrophilic Interaction,Hydrophilicities,Hydrophobic Interaction,Hydrophobicities,Interaction, Hydrophilic,Interaction, Hydrophobic,Interactions, Hydrophilic,Interactions, Hydrophobic

Related Publications

Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
May 2016, European journal of medicinal chemistry,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
October 2015, Bioorganic chemistry,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
January 2016, Central nervous system agents in medicinal chemistry,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
December 2020, Journal of enzyme inhibition and medicinal chemistry,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
December 2004, Journal of medicinal chemistry,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
December 2019, Bioorganic chemistry,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
December 2012, Bioorganic & medicinal chemistry letters,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
April 2019, Archiv der Pharmazie,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
November 2019, Bioorganic chemistry,
Marco Mellado, and César González, and Jaime Mella, and Luis F Aguilar, and Dolores Viña, and Eugenio Uriarte, and Mauricio Cuellar, and Maria J Matos
February 2010, Bioorganic & medicinal chemistry,
Copied contents to your clipboard!