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      Proposed Mechanism for the Antitrypanosomal Activity of Quercetin and Myricetin Isolated from Hypericum afrum Lam.: Phytochemistry, In Vitro Testing and Modeling Studies

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          Abstract

          The in vitro activity of L. donovani (promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells) and T. brucei, from the fractions obtained from the hydroalcoholic extract of the aerial part of Hypericum afrum and the isolated compounds, has been evaluated. The chloroform, ethyl acetate and n-butanol extracts showed significant antitrypanosomal activity towards T. brucei, with IC 50 values of 12.35, 13.53 and 12.93 µg/mL and with IC 90 values of 14.94, 19.31 and 18.67 µg/mL, respectively. The phytochemical investigation of the fractions led to the isolation and identification of quercetin ( 1), myricitrin ( 2), biapigenin ( 3), myricetin ( 4), hyperoside ( 5), myricetin-3- O-β- d-galactopyranoside ( 6) and myricetin-3’- O-β- d-glucopyranoside ( 7). Myricetin-3’- O-β- d-glucopyranoside ( 7) has been isolated for the first time from this genus. The chemical structures were elucidated by using comprehensive one- and two-dimensional nuclear magnetic resonance (1D and 2D NMR) spectroscopic data, as well as high-resolution electrospray ionization mass spectrometry (HR-ESI–MS). These compounds have also been evaluated for their antiprotozoal activity. Quercetin ( 1) and myricetin ( 4) showed noteworthy activity against T. brucei, with IC 50 and IC 90 values of 7.52 and 5.71 µM, and 9.76 and 7.97 µM, respectively. The T. brucei hexokinase (TbHK1) enzyme was further explored as a potential target of quercetin and myricetin, using molecular modeling studies. This proposed mechanism assists in the exploration of new candidates for novel antitrypanosomal drugs.

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          ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB.

          Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reproduction of NMR χ1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.
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            Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.

            Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 A in nearly half of the cases and are greater than 2 A in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
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              Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.

              A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                14 February 2021
                February 2021
                : 26
                : 4
                : 1009
                Affiliations
                [1 ]Département de Chimie, Faculté des Sciences Exactes, Université des Frères Mentouri Constantine 1, Constantine 25000, Algeria
                [2 ]Department of BioMolecular Sciences, Division of Medicinal Chemistry, University of Mississippi, University, MS 38677, USA; jleon@ 123456mailbox.sc.edu (F.L.); sjcutler@ 123456cop.sc.edu (S.J.C.)
                [3 ]Department of Chemistry, Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122, USA; kelokely@ 123456temple.edu (K.M.E.); mnael@ 123456pharm.tanta.edu.eg (M.A.N.)
                [4 ]Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
                [5 ]Laboratoire de Synthèse Organique, Modélisation et Optimisation des Procèdes (LOMOP), Université Badji Mokhtar, Annaba 23000, Algeria; samira.benyahia13@ 123456gmail.com
                [6 ]Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
                [7 ]Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, Riyadh 13713, Saudi Arabia
                [8 ]Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Cairo 11371, Egypt
                Author notes
                [* ]Correspondence: laritfarida@ 123456umc.edu.dz (F.L.); mghoneim@ 123456mcst.edu.sa (M.M.G.); Tel.: +966-537415011 (F.L. & M.M.G.)
                Author information
                https://orcid.org/0000-0002-1396-0719
                https://orcid.org/0000-0002-2394-021X
                https://orcid.org/0000-0002-5064-2381
                Article
                molecules-26-01009
                10.3390/molecules26041009
                7918497
                33672916
                6ca207a8-2f8c-43ae-8235-3313f3f9b0e0
                © 2021 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
                : 14 January 2021
                : 10 February 2021
                Categories
                Article

                antitrypanosomal,antileishmanial,hexokinase (tbhk1),docking,flavonoids,hypericum afrum

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