The binding pose and affinity between a ligand and enzyme are very important pieces of information for computer-aided drug design. In the initial stage of a drug discovery project, this information ...is often obtained by using molecular docking methods. Autodock4 and Autodock Vina are two commonly used open-source and free software tools to perform this task, and each has been cited more than 6000 times in the last ten years. It is of great interest to compare the success rate of the two docking software programs for a large and diverse set of protein–ligand complexes. In this study, we selected 800 protein–ligand complexes for which both PDB structures and experimental binding affinity are available. Docking calculations were performed for these complexes using both Autodock4 and Autodock Vina with different docking options related to computing resource consumption and accuracy. Our calculation results are in good agreement with a previous study that the Vina approach converges much faster than AD4 one. However, interestingly, AD4 shows a better performance than Vina over 21 considered targets, whereas the Vina protocol is better than the AD4 package for 10 other targets. There are 16 complexes for which both the AD4 and Vina protocols fail to produce a reasonable correlation with respected experiments so both are not suitable to use to estimate binding free energies for these cases. In addition, the best docking option for performing the AD4 approach is the long option. However, the short option is the best solution for carrying out Vina docking. The obtained results probably will be useful for future docking studies in deciding which program to use.
The main protease (Mpro) of the novel coronavirus SARS-CoV-2, which has caused the COVID-19 pandemic, is responsible for the maturation of its key proteins. Thus, inhibiting SARS-CoV-2 Mpro could ...prevent SARS-CoV-2 from multiplying. Because new inhibitors require thorough validation, repurposing current drugs could help reduce the validation process. Many recent studies used molecular docking to screen large databases for potential inhibitors of SARS-CoV-2 Mpro. However, molecular docking does not consider molecular dynamics and thus can be prone to error. In this work, we developed a protocol using free energy perturbation (FEP) to assess the potential inhibitors of SARS-CoV-2 Mpro. First, we validated both molecular docking and FEP on a set of 11 inhibitors of SARS-CoV-2 Mpro with experimentally determined inhibitory data. The experimentally deduced binding free energy exhibits significantly stronger correlation with that predicted by FEP (
R
= 0.94 ± 0.04) than with that predicted by molecular docking (
R
= 0.82 ± 0.08). This result clearly shows that FEP is the most accurate method available to predict the binding affinity of SARS-CoV-2 Mpro + ligand complexes. We subsequently used FEP to validate the top 33 compounds screened with molecular docking from the ZINC15 database. Thirteen of these compounds were predicted to bind strongly to SARS-CoV-2 Mpro, most of which are currently used as drugs for various diseases in humans. Notably, delamanid, an anti-tuberculosis drug, was predicted to inhibit SARS-CoV-2 Mpro in the nanomolar range. Because both COVID-19 and tuberculosis are lung diseases, delamanid has higher probability to be suitable for treating COVID-19 than other predicted compounds. Analysis of the complexes of SARS-CoV-2 Mpro and the top inhibitors revealed the key residues involved in the binding, including the catalytic dyad His14 and Cys145, which is consistent with the structural studies reported recently.
Free Energy Pertubation (FEP) can be used to accurately predict the binding affinity of a ligand to the main protease (Mpro) of the novel coronavirus SARS-CoV-2.
Originating for the first time in Wuhan, China, the outbreak of SARS-CoV-2 has caused a serious global health issue. An effective treatment for SARS-CoV-2 is still unavailable. Therefore, in this ...study, we have tried to predict a list of potential inhibitors for SARS-CoV-2 main protease (Mpro) using a combination of molecular docking and fast pulling of ligand (FPL) simulations. The approaches were initially validated over a set of eleven available inhibitors. Both Autodock Vina and FPL calculations produced consistent results with the experiments with correlation coefficients of
R
Dock
= 0.72 ± 0.14 and
R
W
= −0.76 ± 0.10, respectively. The combined approaches were then utilized to predict possible inhibitors that were selected from a ZINC15 sub-database for SARS-CoV-2 Mpro. Twenty compounds were suggested to be able to bind well to SARS-CoV-2 Mpro. Among them, five top-leads are
periandrin V
,
penimocycline
,
cis-p-Coumaroylcorosolic acid
,
glycyrrhizin
, and
uralsaponin B
. The obtained results could probably lead to enhance the COVID-19 therapy.
A combination of Autodock Vina and FPL calculations suggested that
periandrin V
,
penimocycline
,
cis-p-Coumaroylcorosolic acid
,
glycyrrhizin
, and
uralsaponin B
are able to bind well to SARS-CoV-2 Mpro.
Biocompatible microlasers, generally made of bio-derived materials, are promising for biosensing and cell-tracking. These kinds of lasers offer favourable opportunities like biocompatibility and ...biodegradability but the materials used often require complicated synthesis and high cost. In this work, we demonstrate that polyvinyl alcohol (PVA), a synthetic water-soluble low-cost polymer, with fascinating properties such as good transparency, biocompatibility, biodegradability is an excellent candidate for making laser cavity. Using a simple and effective technique, dye-doped PVA microspheres can be fabricated with various sizes from 10 to 200 μm. These microspheres can act as excellent lasers under optical excitation with a lasing threshold of ∼2 μJ/mm2 and Q factor of lasing modes of ∼3000. The lasing mechanism is studied and it is ascribed to whispering gallery mode (WGM). Size-dependent lasing characteristics including lasing spectrum, quality (Q) factor and lasing threshold are investigated. Owing to the ease of fabrication, the cost-effectiveness, the biocompatibility of the PVA material, our biocompatible microlasers are promising for future biosensing applications.
Essential oils are promising as environmentally friendly and safe sources of pesticides for human use. Furthermore, they are also of interest as aromatherapeutic agents in the treatment of ...Alzheimer’s disease, and inhibition of the enzyme acetylcholinesterase (AChE) has been evaluated as an important mechanism. The essential oils of some species in the genera Callicarpa, Premna, Vitex and Karomia of the family Lamiaceae were evaluated for inhibition of electric eel AChE using the Ellman method. The essential oils of Callicarpa candicans showed promising activity, with IC50 values between 45.67 and 58.38 μg/mL. The essential oils of Callicarpa sinuata, Callicarpa petelotii, Callicarpa nudiflora, Callicarpa erioclona and Vitex ajugifolia showed good activity with IC50 values between 28.71 and 54.69 μg/mL. The essential oils Vitex trifolia subsp. trifolia and Callicarpa rubella showed modest activity, with IC50 values of 81.34 and 89.38, respectively. trans-Carveol showed an IC50 value of 102.88 µg/mL. Molecular docking and molecular dynamics simulation were performed on the major components of the studied essential oils to investigate the possible mechanisms of action of potential inhibitors. The results obtained suggest that these essential oils may be used to control mosquito vectors that transmit pathogenic viruses or to support the treatment of Alzheimer’s disease.
Four lignans, asarinin (1), horsfieldin (2), 5-(4-(3,4,5-trimethoxyphenyl)hexahydrofuro3,4-cfuran-1-yl)benzod1,3dioxole (3), 5-(4-(3,5-dimethoxyphenyl)hexahydrofuro3,4-cfuran-1-yl)benzod1,3dioxole ...(4), and four non-alkaloid compounds, piperonylic acid (5), hesperidin (6), syringin (7), and β-sitosterol (8) were isolated from the stem bark of Zanthoxylum rhetsa grown in Vietnam. Their chemical structures were elucidated by spectroscopic analysis and compared with the references. Except for compound 6, all the remaining compounds (1–5, 7, and 8) were isolated for the first time from Z. rhetsa. The isolated compounds were tested for their cytotoxic activity against three human cancer cell lines, LU-1, Hep-G2, and KB. Compound 5 showed moderate cytotoxic activity against all three cell lines with IC50 values ranging from 48.13 to 49.06 µg mL−1. Notably, compound 6 demonstrated selective cytotoxicity against LU-1, Hep-G2, and KB cancer cell lines (IC50 66.48–67.41 µg mL−1) while non-toxic toward normal Vero cell. Compound 6 also exhibited its ability to inhibit main protease (Mpro) enzyme in vitro with an IC50 value of 55.49 µg mL−1 and in silico with the binding affinity toward targeted protein of −14.36 kcal mol−1.
The addition of chalcone and amine components into indirubin-3'-oxime resulted in 15 new derivatives with high yields. Structures of new derivatives were also elucidated through 1D, 2D-NMR and ...HR-MS(ESI) spectra and X-ray crystallography. All designed compounds were screened for cytotoxic activity against four human cancer cell lines (HepG2, LU-1, SW480 and HL-60) and one human normal kidney cell line (HEK-293). Compound 6f exhibited the most marked cytotoxicity meanwhile cytotoxicity of compounds 6e, 6h and 6l was more profound toward cancer cell lines than toward normal cell. These new derivatives were further analyzed via molecular docking studies on GSK-3β enzyme. Docking analysis shows that most of the derivatives exhibited potential inhibition activity against GSK-3β with characteristic interacting residues in the binding site. The fast pulling of ligand scheme was then employed to refine the binding affinity and mechanism between ligands and GSK-3β enzyme. The computational results are expected to contribute to predicting enzyme target of the trial inhibitors and their possible interaction, from which the design of new cytotoxic agents could be created in the future.
In this study, we combined g-C3N4 and NiWO4 to establish g-C3N4/NiWO4 composites for removal of gaseous toluene. The obtained characterization and toluene removal results indicated that the ...photocatalytic activities of the established g-C3N4/NiWO4 were much higher than that of the single component. A direct Z scheme mechanism is proposed for the enhancement. Because of the intimate integration between g-C3N4 and NiWO4, the photo-excited electrons in the conduction band of the NiWO4 tends to combine with photo-excited holes in the valence band of the g-C3N4 preserving the existence of electrons in the conduction band of the g-C3N4 and holes in the valence band of the NiWO4. Therefore, the established g-C3N4/NiWO4 system could produce significant amounts of available electrons and holes for photocatalytic degradation of toluene even under visible light. Among established g-C3N4/NiWO4 materials, the 1C/1N material, which the mole ratio of g-C3N4 was equal to that of NiWO4, exhibited the highest photocatalytic degradation of toluene. The maximum removal efficiency and mineralization degree of toluene by 1C/1N were 95.3% and 99.1%, respectively. We also investigated that the prepared g-C3N4/NiWO4 materials exhibited high stability during long-term toluene removal.
Photocatalytic mechanism of g-C3N4/NiWO4 for degradation of gaseous toluene under visible light Display omitted
•g-C3N4/NiWO4 Z direct scheme system were successfully established.•Z-scheme prevented fast recombination of e- and h+ and remained their oxidative ability.•The established materials exhibited excellent photocatalytic degradation of gaseous toluene.•The optimal mole ratio of g-C3N4/(NiWO4 + g-C3N4) for toluene removal was 50%.•The 1C/1N removed 95.3% toluene and mineralized 99.1% of them into CO2 and H2O.
AutoDock Vina (Vina) achieved a very high docking‐success rate, p^, but give a rather low correlation coefficient, R, for binding affinity with respect to experiments. This low correlation can be an ...obstacle for ranking of ligand‐binding affinity, which is the main objective of docking simulations. In this context, we evaluated the dependence of Vina R coefficient upon its empirical parameters. R is affected more by changing the gauss2 and rotation than other terms. The docking‐success rate p^ is sensitive to the alterations of the gauss1, gauss2, repulsion, and hydrogen bond parameters. Based on our benchmarks, the parameter set1 has been suggested to be the most optimal. The testing study over 800 complexes indicated that the modified Vina provided higher correlation with experiment Rset1=0.556±0.025 compared with RDefault=0.493±0.028 obtained by the original Vina and RVina1.2=0.503±0.029 by Vina version 1.2. Besides, the modified Vina can be also applied more widely, giving R≥0.500 for 32/48 targets, compared with the default package, giving R≥0.500 for 31/48 targets. In addition, validation calculations for 1036 complexes obtained from version 2019 of PDBbind refined structures showed that the set1 of parameters gave higher correlation coefficient (Rset1=0.617±0.017) than the default package (RDefault=0.543±0.020) and Vina version 1.2 (RVina1.2=0.540±0.020). The version of Vina with set1 of parameters can be downloaded at https://github.com/sontungngo/mvina. The outcomes would enhance the ranking of ligand‐binding affinity using Autodock Vina.
A new set of empirical parameters of AutoDock Vina was proposed. The accuracy of affinity prediction was significantly increased from RDefault=0.493±0.028 to Rset1=0.556±0.025 over 800 testing complexes. Over 1036 validating complexes, the proposed parameter formed Rset1=0.617±0.017, which is rigidly larger than the default package (RDefault=0.543±0.020) and Vina version 1.2 (RVina1.2=0.540±0.020).
A new racemic xanthone, garmckeanin A (1), and eight known analogs 2–9 were isolated from the ethyl acetate (AcOEt) extract of the Vietnamese Garcinia mckeaniana leaves. Their structures were ...determined by MS and NMR spectral analyses and compared with the literature. The AcOEt extract showed good cytotoxicity against cancer cell lines KB, Lu, Hep‐G2 and MCF7, with IC50 values of 5.40–8.76 μg/mL, and it also possessed α‐glucosidase inhibitory activity, with an IC50 value of 9.17 μg/mL. Garmckeanin A (1) exhibited inhibition of all cancer cell lines, with an IC50 value of 7.3–0.9 μM. Allanxanthone C (5) successfully controlled KB growth, with an IC50 value of 0.54 μM, higher than that of the positive control, ellipticine (IC50 1.22 μM). Norathyriol (8) was a promising α‐glucosidase inhibitor, with an IC50 value of 0.07 μM, much higher than that of the positive control, acarbose (IC50 161.0 μM). The interactions of the potential α‐glucosidase inhibitors with the C‐ and N‐terminal domains of human intestinal α‐glucosidase were also investigated by molecular docking study. The results indicated that bannaxanthone D (2), garcinone E (4), bannaxanthone E (6), and norathyriol (8) exhibit higher binding affinity to the C‐terminal than to the N‐terminal domain through essential residues in the active sites. In particular, compound 8 could be assumed to be the most potent mixed inhibitor.
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