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      Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

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          Abstract

          A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus ( 1), Polygonum senegalense ( 2 and 3), Bhaphia macrocalyx ( 4), Gardenia ternifolia ( 5), and Psiadia punctulata ( 6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 13 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids ( 1 and 46) and chalcones ( 2 and 3) to MAO-A matched closely with the trend in the experimental IC 50′s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid ( 1) with highly potent inhibition (IC 50 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.

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          OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins.

          The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.
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            Plant polyphenols: chemical properties, biological activities, and synthesis.

            Eating five servings of fruits and vegetables per day! This is what is highly recommended and heavily advertised nowadays to the general public to stay fit and healthy! Drinking green tea on a regular basis, eating chocolate from time to time, as well as savoring a couple of glasses of red wine per day have been claimed to increase life expectancy even further! Why? The answer is in fact still under scientific scrutiny, but a particular class of compounds naturally occurring in fruits and vegetables is considered to be crucial for the expression of such human health benefits: the polyphenols! What are these plant products really? What are their physicochemical properties? How do they express their biological activity? Are they really valuable for disease prevention? Can they be used to develop new pharmaceutical drugs? What recent progress has been made toward their preparation by organic synthesis? This Review gives answers from a chemical perspective, summarizes the state of the art, and highlights the most significant advances in the field of polyphenol research. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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              Novel procedure for modeling ligand/receptor induced fit effects.

              We present a novel protein-ligand docking method that accurately accounts for both ligand and receptor flexibility by iteratively combining rigid receptor docking (Glide) with protein structure prediction (Prime) techniques. While traditional rigid-receptor docking methods are useful when the receptor structure does not change substantially upon ligand binding, success is limited when the protein must be "induced" into the correct binding conformation for a given ligand. We provide an in-depth description of our novel methodology and present results for 21 pharmaceutically relevant examples. Traditional rigid-receptor docking for these 21 cases yields an average RMSD of 5.5 A. The average ligand RMSD for docking to a flexible receptor for the 21 pairs is 1.4 A; the RMSD is < or =1.8 A for 18 of the cases. For the three cases with RMSDs greater than 1.8 A, the core of the ligand is properly docked and all key protein/ligand interactions are captured.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                17 November 2020
                November 2020
                : 25
                : 22
                : 5358
                Affiliations
                [1 ]Department of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USA; nchaurasiya@ 123456southernresearch.org
                [2 ]National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA; ppandey@ 123456olemiss.edu
                [3 ]Department of Chemistry, University of Nairobi, Nairobi P.O. Box 30197-00100, Kenya; jmidiwo@ 123456uonbi.ac.ke
                [4 ]Department of BioMolecular Sciences, Division of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA; rjd@ 123456olemiss.edu
                [5 ]Department of pure and applied Chemistry, Masinde Muliro University of Science and Technology, Kakamega P.O. Box 190-50100, Kenya; rbwire@ 123456mmust.ac.ke
                Author notes
                [* ]Correspondence: milias@ 123456olemiss.edu (I.M.); btekwani@ 123456southernresearch.org (B.L.T.); Tel.: +1-662-915-1051 (I.M.); +1-205-581-2205 (B.L.T.)
                Author information
                https://orcid.org/0000-0001-9128-8254
                https://orcid.org/0000-0002-3789-1842
                https://orcid.org/0000-0003-4545-4316
                Article
                molecules-25-05358
                10.3390/molecules25225358
                7697615
                33212830
                a874cae9-d6d6-47e9-b456-6ab98b260ffb
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 September 2020
                : 09 November 2020
                Categories
                Article

                recombinant monoamine oxidase-a,monoamine oxidase-b,neurological disorder,enzyme kinetics,molecular docking,inhibition activity,flavonoid

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