DOI: 10.6084/m9.figshare.7963577
title: Known compounds and new lessons: structural and electronic basis of flavonoid-based bioactivities

description: Flavonoids correspond to a major class of polyphenolic phytochemicals with flavone as major parent scaffold. This class of compounds is attributed with very rich nutritional as well as therapeutic values. The present study focuses on a panel of 16 flavonoid molecules that are demonstrated to exhibit various bioactivities like anti-angiogenic, anti-inflammatory as well as possess antioxidant potential. The electronic basis of these bioactivities is rarely explored, and structural basis of flavonoid-induced cyclooxygenase (COX) inhibition has still remained an uncharted area. The current report thus focuses on providing an electronic explanation of these bioactivities using density functional theory-based quantum chemical descriptors. We also attempt to provide a structure–activity relation model for COX by inhibition of these 16 flavonoids using molecular docking. Here, we report molecular dynamics data from 16 flavonoid–COX-2 complexes performed for 50 nanoseconds each that demonstrates key structural and dynamic aspects of flavonoid-based COX inhibition in light of observed experimental facts. Interaction analysis and evaluation of side-chain dynamics presented in current study are well in agreement with the empirical study and is hoped to pave new avenues towards design and development of COX-2 selective chemical agents. Abbreviations2′HFN-2′hydroxy flavonone2D2 dimension3D3 dimension3H7MF3-hydroxy-7-methoxy flavone4′HFN-4′hydroxy flavonone4′MF- 4′methoxy flavone7HFN7-hydroxy flavononeCHARMMChemistry at Harvard Macromolecular MechanicsCOXcyclooxygenaseCOX-1cyclooxygenase-1COX-2cyclooxygenase-2DMdipole momentDPPH- 2, 2diphenyl-1-picryl hydrazineEAelectron affinitiesEGFRepidermal growth factor receptorE-HOMOHighest occupied molecular orbital energyE-LUMOLowest unoccupied molecular orbital energyEPAeicosapentaenoic acidFROG2FRee Online druG conformation generationGAGenetic AlgorithmGROMACSGROningen MAchine for Chemical SimulationsHOMOHighest occupied molecular orbitalIPIonization potentialLOMOLowest unoccupied molecular orbitalMDMolecular dynamicsMOMolecular orbitalNAMDNanoscale Molecular DynamicsNSAIDsNon-Steroidal Anti Inflammatory DrugsNsnanosecondsNVEEnsemble-constant-energy, constant-volume, Constant particle ensemblePDB-IDProtein Data Bank IdentifierPMEParticle Mesh EwaldPyRXPython PrescriptionRMSDRoot-Mean-Square DeviationRMSFRoot-Mean-Square FluctuationRLSreactive lipid speciesROSReactive Oxygen SpeciesSASAsolvent accessible surface areaSMILESsimplified molecular-input line-entry systemSORsuperoxide anion radicalUFFUniversal force fieldVEGFvascular endothelial growth factorVEGFRvascular endothelial growth factor receptorVMDVisual molecular dynamics hydroxy flavonone 2 dimension 3 dimension 3-hydroxy-7-methoxy flavone hydroxy flavonone methoxy flavone 7-hydroxy flavonone Chemistry at Harvard Macromolecular Mechanics cyclooxygenase cyclooxygenase-1 cyclooxygenase-2 dipole moment diphenyl-1-picryl hydrazine electron affinities epidermal growth factor receptor Highest occupied molecular orbital energy Lowest unoccupied molecular orbital energy eicosapentaenoic acid FRee Online druG conformation generation Genetic Algorithm GROningen MAchine for Chemical Simulations Highest occupied molecular orbital Ionization potential Lowest unoccupied molecular orbital Molecular dynamics Molecular orbital Nanoscale Molecular Dynamics Non-Steroidal Anti Inflammatory Drugs nanoseconds Ensemble-constant-energy, constant-volume, Constant particle ensemble Protein Data Bank Identifier Particle Mesh Ewald Python Prescription Root-Mean-Square Deviation Root-Mean-Square Fluctuation reactive lipid species Reactive Oxygen Species solvent accessible surface area simplified molecular-input line-entry system superoxide anion radical Universal force field vascular endothelial growth factor vascular endothelial growth factor receptor Visual molecular dynamics Communicated by Ramaswamy H. Sarma