The aromatic α,β-unsaturated carbonyl compounds are known to possess biological and pharmacological activities, such as antioxidative, antibacterial, and antiviral effects. We tested the affinities of six new compounds to bind to the catalytic site of the dihydrofolate reductase enzyme. The binding modes of 1-aryl-(3-substitutedquinolyl)-prop-2-en-1-one analogues to the active site of the dihydrofolate reductase are investigated with ligand docking calculations. Docking simulations indicated that these compounds have the same binding modes for dihydrofolate reductase as methotrexate.
Host−guest binding selectivity of the perethylated pillar [5]arene (EtP5A) macrocycles with aliphatic modi ed hydrocarbons, i.e., octane, 1,7-octadiene, and 1,7-octadiyne as guests, has been investigated computationally employing molecular docking simulations. Density Functional Theory (DFT) investigations were also performed on these host-guest complexes using the dispersion-corrected approach BLYP-D3(BJ)/TZP/COSMO calculations as implemented in the ADF program and two dispersion-corrected density functionals, ωB97XD and B97D, along with the 6-311G* basis set, coupled with the PCM solvation model as implemented in the Gaussian software. We performed analysis of the frontier molecular orbitals (FMO) and Natural Bond Orbitals (NBO), Energy Decomposition Analysis (EDA), and Non-Covalent Interaction (NCI-RDG) analysis. The study sheds light on the structures and binding energetics of EtP5A with the above-mentioned guests as well as on the physicochemical nature of the noncovalent interactions involved in these host-guest inclusion complexes. Based on the docking simulations, the EtP5A host revealed slightly better binding ability in the complex with the alkyne guest than with the octane and alkene, corroborated by the EDA analysis. The results showed that the complexation of EtP5A with the hydrocarbons is mainly governed by the interplay of electrostatic interactions and dispersive noncovalent interactions. These results agree well with NCI-RDG and NBO analysis showing that host − guest binding interactions result predominantly from electrostatic CH•••π and van der Waals forces, the H-bonding being weak or not observed. The results obtained using different computational methods were found to be in good agreement and complementary.The three-dimensional EtP5A host-guest complexes including the hydrocarbon molecules, octane, 1,7octadiene, and 1,7-octadiyne, were generated from the pdb format using Autodock-Vina software [46], which allows to predict the binding free energy of complexes. The EtP5A host was used as a rigid receptor, and Autodock Tools [47] was used to determine the possible rotations of bonds by molecular docking. During the simulation, the ligands (guest molecules) were docked to the EtP5A with box dimensions set to the grid (22 × 24 × 24) Å 3 in volume, and the cartesian coordinates center was set to 0.017, -0.021, and − 0.097 Å. The docking con guration with the highest free-energy score (ΔG) was used as the starting geometry conformations for the DFT calculations.The structures of all species, including the host, the guests, and their three complexes, generated by Autodock Tools docking simulations, were reoptimized in both gas and implicit solvent phases using the DFT approaches as implemented in two quantum chemistry programs: Amsterdam Density Functional ADF2021.107 program release [48, 49] and the Gaussian 09 program package [50].
The outbreak of the current pandemic and the evolution of virus resistance against standard drugs led to the emergency of new and potent antiviral agents. Owing to its crucial role in viral replication, the protease enzyme is taken into survey to be a promising target for antiviral drug therapy using computational methods. In order to bring this important class of natural products in the limelight of research for prospective application as chemotherapeutic agents, the anti-SARS-CoV-2 activity of some bioactive molecules obtained from Arbutus serratifolia Salisb which is an Algerian medicinal plant, was investigated using in-silico methods. The molecular docking was performed by AutoDock Vina and UCSF Chimera, as well as ADMET and drug-likeness properties of these molecules were calculated using preADMET web-based application and the Swiss ADME server respectively. The phytochemicals (from Pr(1) to Pr(12)) were tested for their pharmacokinetic properties and docked into the main protease binding site on (PDB ID: 6Y84) in order to find a promising antiviral ligand. All tested molecules induced binding affinities into the binding pocket of (PDB ID: 6Y84) with energy scores ranging from moderate to better (from −6.4 to −8.00 kcal/mol). It is worthy to note that both Pr(2): (1S,5R,6S,8S,9S)-6,8-Dihydroxy-8-methyl-1,5,6,7,8,9-hexahydrocyclopenta [c] pyran-1-yl-β-D-glucopyranoside and Pr(7): ((1S,5S,6S,9S)-1-(β-D-Glucopyranosyloxy)-14-oxo-1,5,6,9-tetrahydro-1H-2,15-dioxacyclopenta [cd] inden-8-yl) methyl acetate, were found to be the best inhibitors with binding affinities (−7.7 kcal/mol and −8.0 kcal/mol), respectively, by virtue of the fact that all these tested molecules exhibited good binding affinities compared with those of Ritonavir and Nirmatrelvir (−1.73 and −1.93 kcal/mol), respectively, which are used as standard antiviral drugs to prevent viral growth. The amino acids: His-163; Glu-166; Arg-188; Thr-190 and Gln-192 represent the key residues of the interaction of SARS-CoV-2 main protease with Pr(7). Furthermore, the results of pharmacodynamic and pharmacokinetic investigations revealed that Pr(6), Pr(8) and Pr(9) uphold the drug-likeness criteria and more particularly, these substances can be absorbed by the human intestine. In addition, all these molecules were shown to be neither hepatotoxic nor significantly noxious to human organism. These natural products are therefore promising inhibitor candidates of viral main protease. However, further in-vitro, in-vivo and even clinical assays are required to probe their functional mechanisms and then to assess their antiviral potency against COVID-19.
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