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•Human histone deacetylase 6 (HDAC6) is a well-validated target for anticancer drug design and development.•Structure-based virtual screening of ∼72 461 druglike compounds retrieved ...from Otava database.•A total of 4 potential HDAC6-selective inhibitors were identified.•Molecular dynamics simulation of their complexes with HDAC6 suggested their stable binding mode over time.
Human histone deacetylase 6 (HDAC6) has been shown to play a major role in oncogenic cell transformation via deacetylation of α-tubulin, making it a viable target of anticancer drug design and development. The crystal structure of HDAC6 catalytic domain 2 has been recently made available, providing avenues for structure-based drug design campaign. Here, in our continuous effort to identify potentially selective HDAC6 inhibitors, structure-based virtual screening of ∼72 461 compounds was carried out using Autodock Vina. The top 100 compounds with calculated ΔG < −10 kcal/mol were manually inspected for binding mode orientation. Furthermore, the top 20 compounds with reasonable binding modes were evaluated for selectivity by further docking against HDAC6 and HDAC7 using Autodock4. Four compounds with a carboxylic fragment, displayed potential selectivity for HDAC6 over HDAC7, and were found to have good druglike and ADMET properties. Their docking complexes were then submitted to 10 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software, to examine the stability of ligand binding modes. These predicted inhibitors remained bound to HDAC6 in the presence of water and ions, and the root-mean-square deviation (RMSD), radius of gyration (Rg) and nonbond distance (protein-ligand) profiles suggested that they might be stable over time of the simulation. This study may provide scaffolds for further lead optimization towards the design of HDAC6 inhibitors with improved selectivity.
Cannabinoid receptor type 2 (CB2R) is a member of the class A G protein-coupled receptor (GPCRs) family and a component of the endocannabinoid system that is modulated by the psychoactive chemical ...from Cannabis sativa, partial agonist Δ9-tetrahydrocannabinol (Δ9-THC). Selective activation of CB2R allows for the treatment of inflammatory and immune-related conditions without the psychotropic effects of CB1R. While CB2R-selective agonists are available, CB2R partial agonists are scarce. Hence, the pharmacological difference between CB2R full agonists and partial agonists remains to be deciphered, prompting the search for novel partial agonists. Here, using an induced-fit docking approach, we built a partial agonist Δ9-THC bound CB2R system from the inactive CB2R structure (PDB ID: 5ZTY) and performed microsecond molecular dynamics (MD) simulations. The simulations reveal an upward shift of the “toggle switch” W6.48(258) and minor outward movement of the transmembrane helix 6 (TM6). Dynamic network model identifies a possible communication path between the ligand and the toggle switch” W6.48(258). Furthermore, to identify potential CB2R partial agonists, we conducted structure-based virtual screening of ZINC15 “Druglike” library containing 17,900742 compounds against 3 conformations derived from MD simulation of CB2R complexed with partial agonist Δ9-THC using Glide virtual screening protocol comprising various filters with increasing accuracy. Nine diverse compounds predicted to have high MM-GBSA binding energy scores and good ADMET properties (including high gastrointestinal absorption and low toxicity) are proposed as potential CB2R partial agonists.
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•A partial agonist Δ9-THC bound CB2R system was built from the inactive CB2R structure (PDB ID: 5ZTY).•A ZINC15 “druglike” library containing ∼17 million compounds was virtually screened for CB2R partial agonists.•Based on MM-GBSA calculations and good ADMET filtering, nine compounds are proposed as potential CB2R partial agonists.
Histone deacetylase 6 (HDAC6) contributes to cancer metastasis in several cancers, including triple-negative breast cancer (TNBC)-the most lethal form that lacks effective therapy. Although several ...efforts have been invested to develop selective HDAC6 inhibitors, none have been approved by the FDA. Toward this goal, existing computational studies used smaller compound libraries and shorter MD simulations. Here, we conducted a structure-based virtual screening of ZINC "Druglike" library containing 17,900,742 compounds using a Glide virtual screening protocol comprising various filters with increasing accuracy. The top 20 hits were subjected to molecular dynamics simulation, MM-GBSA binding energy calculations, and further ADMET prediction. Furthermore, enzyme inhibition assay and cell viability assay were performed on six available compounds from the identified hits. C4 (ZINC000077541942) with a good profile of predicted drug properties was found to inhibit HDAC6 (IC50: 4.7 ± 11.6 μM) with comparative affinity to that of the known HDAC6 selective inhibitor Tubacin (TA) in our experiments. C4 also demonstrated cytotoxic effects against triple-negative breast cancer (TNBC) cell line MDA-MB-231 with EC50 of 40.6 ± 12.7 μM comparable to that of TA (2-20 μM). Therefore, this compound, with pharmacophore features comprising a non-hydroxamic acid zinc-binding group, heteroaromatic linker, and cap group, is proposed as a novel HDAC6 inhibitor.
Abstract Benzene sulfonamides are an important biological substituent for several activities. In this study, hybridization of benzene sulfonamide with piperazine derivatives were investigated for ...their antioxidant capacity and enzyme inhibitory potencies. Six molecules were synthesized and characterized. DPPH, ABTS, FRAP, CUPRAC, chelating and phosphomolybdemum assays were applied to evaluate antioxidant capacities. Results show that compounds have high antioxidant capacity and compound 4 has the best antioxidant activity among them. Compound 4 has higher antioxidant activity than references for FRAP (IC 50 : 0.08 mM), CUPRAC (IC 50 : 0.21 mM) and phosphomolybdenum (IC 50 : 0.22 mM) assays. Besides this, compound 4 has moderate DPPH and ABTS antioxidant capacity. Furthermore, enzyme inhibition activities of these molecules were investigated against AChE, BChE, tyrosinase, α -amylase and α -glucosidase enzymes. It was revealed that all compounds have good enzyme inhibitory potential except for α -amylase enzyme. The best inhibitory activities were observed for AChE with compound 5 the same value (IC 50 : 1.003 mM), for BChE with compounds 2 and 5 the same value (IC 50 : 1.008 mM), for tyrosinase compound 4 (IC 50 : 1.19 mM), and for α -glucosidase with compound 3 (IC 50 : 1.000 mM). Docking studies have been conducted with these molecules, and the results correlate well with the inhibitory assays.
The single-point mutation D26E in human β-tubulin is associated with drug resistance seen with two anti-mitotic taxanes (paclitaxel and docetaxel) when used to treat cancers. The molecular mechanism ...of this resistance remains elusive. However, docetaxel and a third-generation taxane, cabazitaxel, are thought to overcome this resistance. Here, structural models of both the wildtype (WT) and D26E mutant (MT) human β-tubulin were constructed based on the crystal structure of pig β-tubulin in complex with docetaxel (PDB ID: 1TUB). The three taxanes were docked into the WT and MT β-tubulin, and the resulting complexes were submitted to three independent runs of 200 ns molecular dynamic simulations, which were then averaged. MM/GBSA calculations revealed the binding energy of paclitaxel with WT and MT β-Tubulin to be −101.5 ± 8.4 and −90.4 ± 8.9 kcal/mol, respectively. The binding energy of docetaxel was estimated to be −104.7 ± 7.0 kcal/mol with the WT and −103.8 ± 5.5 kcal/mol with the MT β-tubulin. Interestingly, cabazitaxel was found to have a binding energy of −122.8 ± 10.8 kcal/mol against the WT and −106.2 ± 7.0 kcal/mol against the MT β-tubulin. These results show that paclitaxel and docetaxel bound to the MT less strongly than the WT, suggesting possible drug resistance. Similarly, cabazitaxel displayed a greater binding propensity against WT and MT β-tubulin than the other two taxanes. Furthermore, the dynamic cross-correlation matrices (DCCM) analysis suggests that the single-point mutation D26E induces a subtle dynamical difference in the ligand-binding domain. Overall, the present study revealed how the single-point mutation D26E may reduce the binding affinity of the taxanes, however, the effect of the mutation does not significantly affect the binding of cabazitaxel.
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•MD simulations were carried out to understand the drug resistance of Taxane drugs bound to human β-tubulin mutant (D26E).•Paclitaxel and docetaxel bound to the MT less strongly than the WT, showing drug resistance.•Similarly, cabazitaxel demonstrated a lower binding affinity for the MT than the WT.•The dynamic cross-correlation matrices analysis suggests that D26E induces a subtle dynamical difference in the ligand-binding domain.
Essential oils are commonly extracted from plants by hydrodistillation in which an aqueous phase called hydrosol is obtained. Like essential oil, this by-product of distillation can be a source of ...natural bioactive molecules with health benefits. This study aimed at the investigation of the chemical profile, antiproliferative and antibacterial activities of essential oil and hexane fraction of hydrosol from Plectrunthus amboinicus (family Lamiacease) fresh leaf cultivated in Sudan. Essential oil was obtained by hydrodistilation and hexane fraction (HF) was derived from hydrosol by liquid –liquid extraction. Results showed that the phenolic monoterpene thymol (72.9%) was the dominant component of the essential oil while the HF was characterized by the presence of long-chain (n-C29 to n-C68) alkanes (91.4%). The HF showed highest antiproliferative activity against the colon cancer HT29 (IC50 9.2 μg/mL) and HCT116 (IC50 7.7 μg/mL) cell lines. The essential oil exerted best antibacterial activity with highest inhibition (22.0–22.3 mm) and minimum inhibitory concentration (31 μg/mL) against the Gram positive bacteria Bacillus subtilis and Staphylococcus aureus. In silico study showed that the major components of the oil displayed higher docking scores than those present in the HF suggesting an antagonistic effect by other molecules in the essential oil. In conclusion, beside the essential oil, the hydrosol possesses promising bioactive composition suggesting that it could be exploited for further therapeutic applications.
•Chemical profile and bioactivity of Plectranthus amboinicus leaf was determined.•Thymol was the most abundant compound of the essential oil (EO).•Hexane fraction (HF) from the hydrosol contained mainly long-chain alkanes.•HF exerted the highest antiproliferative activity against two colon cancer cell lines.•The EO exerted good antibacterial activity against Gram-positive bacteria.
•Extracts and essential oils of four different hops varieties from the territory of Slovenia were obtained.•Monoterpnenes and sesquiterpene hydrocarbons were dominant components in isolated essential ...oils.•All obtained extracts and oils were characterized by strong antimicrobial activity.•All extracts and essential oils were selective towards normal cells.
Hydrophilic, lipophilic extracts and essential oil of four hops varieties from Slovenia were examined in this study. Lipophilic extracts were obtained by supercritical extraction (SFE), while for hydrophilic extracts ultrasound and microwave extraction were employed. Essential oils were isolated by the hydrodistillation process. The lipophilic composition of essential oils and lipophilic extracts was determined by GC–MS analysis. Monoterpenes and sesquiterpene hydrocarbons were the most abundant class of compounds in oils (62.27–79.65 %), with myrcene being the most abundant constituent. Limonene and trans-caryophyllene were two terpenes determined in all essential oils while only trans-caryophyllene was detected in SFE samples. Antioxidant, antimicrobial, and cytotoxic activity, determined by applying in vitro assays, was more influenced by extraction technique than by varieties. Molecular docking was carried out to gain insight into the potential cancer protein targets BCL-2 and MMP9, whereby humulene epoxide II displayed good binding configuration within the cavities of the two proteins.
Glaucosciadium cordifolium (Apiaceae) is traditionally used against stomach ailments, as aphrodisiac and appetizer. This study endeavored to characterize several extracts of G. cordifolium aerial ...parts (prepared by various isolation procedures (ASE: Accelerated solvent extraction; HAE: homogenizer-assisted extract; MAE: Microwave-assisted extraction; MAC: Maceration; SFE: supercritical CO2 extraction; SOX: Soxhlet; UAE: Ultrasound-assisted extraction) and evaluate the antioxidant activity and inhibitory activity against clinical enzymes. In order to describe the composition of the extracts liquid chromatography-mass spectrometry (LC-MS) analysis was employed. Of the total number of confirmed polyphenol components (15 in total), four were dominant in their content: 5-O-caffeoylquinic acid, p-coumaric acid, quercetin-3-O-glucoside and quercetin-3-O-rhamnoside. Spectrophotometric analysis showed that the total phenolic and flavonoid contents differed among the extracts, which was influenced by extraction technique used for their preparation. The phenolic content of the different extracts varied in the order HAE > UAE > MAC > SOX > MAE > ASE > SFE. HAE extract yielded the highest phenolic content (49.97 mg gallic acid equivalent (GAE)/g) while SFE demonstrated the lowest phenolic content (21.65 mg GAE/g). MAC extracts contained the highest flavonoids (50.35 mg rutin equivalent (RE)/g) while SFE extract showed the lowest flavonoid content (10.87 mg RE/g). UAE, MAC, MAE, HAE, SOX and ASE showed significant DPPH antioxidant activities and the values of radical inhibitory capacity varied in the range of 55.79–54.99 mg TE/g. SFE demonstrated weak DPPH (1,1-diphenyl-2-picrylhydrazyl) radical inhibitory activity with a value 7.0 mg TE/g. UAE showed the highest ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) cation radical inhibitory potential (122.41 mg trolox equivalent (TE)/g). The CUPRAC (cupric reducing antioxidant capacity) activity of UAE was remarkable with a value of 193.58 mg TE/g. A gradual decrease in activity was observed with extracts obtained from other extraction techniques with the lowest antioxidant activity (77.0 mg TE/g) obtained from SFE extract. The highest antioxidant recorded by Phosphomolybdenum was found in HAE extract (1.62 mmol TE/g). SFE showed the highest metal chelating activity (27.30 mg ethylenediamine tetraacetic acid (EDTAE)/g). Regarding the acetylcholinesterase (AChE) inhibitory activity, MAE and ASE extracts showed the highest potential with a value of 4.06 and 4.05 mg galanthamine equivalent (GALAE)/g respectively. All tested extracts showed considerable whitening activity and SFE revealed the highest activity against tyrosinase (93.82 mg kojic acid equivalent (KAE)/g). In addition, SFE showed the best inhibitory ability against amylase (0.71 mmol acarbose equivalent (ACAE)/g). However, the extracts had similar glucosidase inhibitory effects (1.64–1.71 mmol ACAE/g). The rich chemical composition of the extracts and joint action of different classes of polyphenolic compounds in them may be responsible for their high biological activity. Extracts with the highest activity could serve in the future as an important tool for controlling the activity of clinically important enzymes and take their place in the official formulation after additional pharmacological tests.
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•Glaucosciadium cordifolium extracts were prepared by using different extraction methods.•5-O-caffeoylquinic acid, p-coumaric acid, quercetin-3-O-glucoside were dominant components in LC-MS analysis.•Non-conventional techniques were more effective than traditional methods.•The results could provide novel informations for preparing bio-formulations in nutraceutical industry.
Interleukin (IL)-33 is a cytokine implicated in several inflammatory and autoimmune diseases. Upon binding to its receptor ST2, IL-33 activates allergic inflammatory responses. To block this ...protein-protein interaction with a potential anti-allergic agent, we screened Universal Natural Product Database (UNPD) using a combined approach of molecular docking and dynamic simulations. Six hundred compounds with high gastrointestinal absorption properties from the UNPD were retrieved and subjected to molecular docking using Autodock Vina, out of which four hetero-cyclic compounds (UNPD36, UNPD2045, UNPD8905, UNPD122514) were found to have binding energy score of < −7.0 Kcal/mol. Further analysis from 100 ns MD simulation of the best hit (UNPD36) revealed that IL-33_UNPD36 complex reached average stability at RMSD of 2.7 Å, and residues involved in the interaction showed lower fluctuations compared to the residues at the β4-β5 and β11-β12 loop region. Further molecular docking using Autodock 4.2 was carried out to determine the binding orientation of UNPD36. Using GROMACS, additional 50 ns MD simulations and MM-PBSA calculation were performed on this complex. Finally, chemoinformatic studies revealed that the UNPD36 had drug-like and pharmacokinetic profiles as well as potentials for oral and topical applications, in addition to good safety profile. Thus, it was concluded that a hetero-cyclic compound with chromone moiety (UNPD36) had a good and stable binding mode to serve as potential inhibitor of IL-33 and/or may provide a scaffold for further optimization toward the design of more potent inhibitors for application in the treatment of respiratory allergies.
Communicated by Ramaswamy H. Sarma
