AbstractThe oncogenic kinase PAK1 (p21-activated kinase 1) is involved in developing many diseases including cancers, neurofibromatosis, Alzheimer's disease, diabetes (type 2), and hypertension. Thus, it is thought to be a prominent therapeutic target, and its selective inhibitors have a huge market potential. Recently, herbal PAK1 inhibitors have gained immense interest over synthetic ones mainly due to their non-toxic effects. Till date, many herbal compounds have been suggested to inhibit PAK1, but their information on selectivity, bioavailability, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, and molecular interactions with PAK1 has not been explored. Hence, this study was designed with computational approaches to explore and identify the best herbal PAK1-blockers showing good ADMET properties, druggable features and binding affinity with PAK1. Herbal inhibitors reported here were initially filtered with Lipinski’s rule of five (RO5). Then, molecular docking between these inhibitors and PAK1 catalytic sites was performed using AutoDock Vina and GOLD suite to determine the binding affinity and interactions. Finally, 200?ns molecular dynamics (MD) simulations on three top-ranked inhibitors including cucurbitacin I (C-I), nymphaeol A (NA), and staurosporine (SPN) were carried out. The binding free energies and interactions revealed that NA can strongly bind with the PAK1 catalytic cleft. PASS prediction and ADMET profiling supported that NA is appeared to be a more selective and safer inhibitor than C-I and SPN. These results conform to the previous experimental evidences, and therefore, NA from Okinawa propolis could be a promising inhibitor for treating PAK1-dependent illnesses.Communicated by Ramaswamy H. Sarma 相似文献
Cyclooxygenase-2 (COX-2) is an important enzyme responsible for the formation of potent inflammatory mediators like prostaglandins, prostacyclin and thromboxane. Hence, inhibition of COX-2 is one of the best ways to control the inflammation. Non-steroidal anti-inflammatory drugs can control inflammation by inhibiting Cyclooxygenase. Selective inhibition of COX-2 is preferable over the inhibition of COX-1 because of the fewer adverse effects produced. Molecular modeling and docking of 134 selected indole compounds were done against COX-2. The pharmacophore-based in silico structural modifications of the best scored compounds were carried out in order to enhance the binding affinity and selectivity. The modification resulted in derivatives with better binding energies than that of known COX-2 inhibitors. The four best derivatives in terms of the binding energies were selected and their binding stabilities were studied by molecular dynamics simulation methods. 相似文献
AbstractDrug discovery for a vigorous and feasible lead candidate is a challenging scientific mission as it requires expertise, experience, and huge investment. Natural products and their derivatives having structural diversity are renowned source of therapeutic agents since many years. Tyrosol (a natural phenylethanoid) has been extracted from olive oil, and its structure was confirmed by elemental analysis, FT-IR, FT-NMR, and single crystal X-ray crystallography. The conformational analysis for tyrosol geometry was performed by Gaussian 09 in terms of density functional theory. Validation of bond lengths and bond angles obtained experimentally as well as theoretically were performed with the help of curve fitting analysis, and values of correlation coefficient (R) obtained as 0.988 and 0.984, respectively. The charge transfer within the tyrosol molecule was confirmed by analysis of HOMO→LUMO molecular orbitals. In molecular docking with COX-2 (PDB ID: 5F1A), tyrosol was found to possess satisfactory binding affinity as compared to other NSAIDs (Aspirin, Ibuprofen, and Naproxen) and a COX-2 selective drug (Celecoxib). ADMET prediction, drug-likeness and bioactivity score altogether confirm the lead/drug like potential of tyrosol. Further investigation of simulation quality plot, RMSD and RMSF plots, ligands behavior plot as well as post simulation analysis manifest the consistency of 5F1A-tyrosol complex throughout the 20?ns molecular simulation process that signifies its compactness and stability within the receptor pocket. Abbreviations ADMET Absorption, Distribution, Metabolism, Excretion and Toxicity Å Angstrom COX-2 Cyclooxygenase-2 DFT Density Functional Theory DMF Dimethylformamide FMO Frontier Molecular Orbital FT-IR Fourier-transform Infrared Spectroscopy FT-NMR Nuclear Magnetic Resonance Spectroscopy HOMO Highest Occupied Molecular Orbital LUMO Lowest Unoccupied Molecular Orbital MD Molecular Dynamics NS Nanosecond NSAIDs Non-steroidal anti-inflammatory drugs OPE Osiris Property Explorer RMSD Root-Mean-Square Deviation RMSF Root Sean Square Fluctuation Communicated by Ramaswamy H. Sarma 相似文献
Natural products acquire massive structural and chemical diversity, which cannot be coordinated by any synthetic libraries for small molecules and they are continuing to inspire novel discoveries in health sciences. We have performed the computational calculations for geometry optimization and prediction of electronic and structural properties of some plant phenolic compounds through Gaussian 09 program. Energies of molecular orbitals were computed, to mimic out the stabilities arising from charge delocalization and intramolecular interactions. This process indicated the eventual charge transfer within the molecules. The molecular docking and ADMET properties of these compounds with a novel anticancer (HER2) and anti-inflammatory (COX-2) targets revealed that two molecules were capable of inhibiting both the targets, and could be used as multi target inhibitors. Furthermore, molecular dynamics simulation studies were performed to elucidate the binding mechanism and the comparison of inhibitor’s binding mode with diverse biological activities as anticancer and anti-inflammatory agents. A high-quality association was reported among quantum chemical, ADMET, docking, dynamics and MMGBSA results.
We recently reported that the hydroxyiminoethanone derivative, (E)-OXM, behaves as a highly selective COX-1 inhibitor (COX-1 SI = 833), and also an interesting scaffold with unique characteristics. In the current study, a comprehensive crystallographic and computational study was performed to elucidate its conformational stability and pharmacological activity. Its conformational energy was studied at the B3LYP/6-311G** level of theory and compared to the single-crystal X-ray diffraction data. In addition, computational studies of three structurally different stilbenoid derivatives used as selective COX-1 or COX-2 inhibitors were undertaken to predict their COX selectivity potentials. Flexible docking was performed for all compounds at the active site of both COX-1 and COX-2 enzymes by considering some of the key residues as flexible during the docking operation. In the next step, molecular dynamic simulation and binding free energy calculations were performed by MM-PBSA. Final results were found to be highly dependent on the atomic charges of the inhibitors and the choice of force field used to calculate the atomic charges. The binding conformation of the hydroxyiminoethanone derivative is highly correlated with the type of COX isoform inhibited. Our predictive approach can truly predict the cyclooxygenase inhibition selectivity of stilbenoid inhibitors. 相似文献
Cyclooxygenase-2 (COX-2) produces prostaglandins in inflamed tissues and hence has been considered as an important target for the development of anti-inflammatory drugs since long. Administration of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity. The present study involves developing a virtual library of novel molecules with high druglikeliness using structure-based de novo drug designing and 2D fingerprinting approach. A library of 2657 drug like molecules was generated. 2D fingerprinting based screening of the designed library gave a unique set of compounds. Molecular docking approach was then used to identify two compounds highly specific for COX-2 isoform. Molecular dynamics simulations of protein-ligand complexes revealed that the candidate ligands were dynamically stable within the cyclooxygenase binding site of COX-2. The ligands were further analyzed for their druglikeliness, ADMET properties and synthetic accessibility using knowledge based set of rules. The results revealed that the molecules are predicted to selectively bind to COX-2 enzyme thereby potentially overcoming the limitations posed by the drugs in clinical use. 相似文献
Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes.
BackgroundCyclooxygenase-2 (COX-2) is an important enzyme with numerous biological functions. Overexpression of COX-2 has been associated with various inflammatory-related diseases and therefore, projected as an important pharmacological target.PurposeWe aimed to investigate the inhibitory potential of isolated bioactive compounds, 3-caffeoyl-4-dihydrocaffeoyl quinic acid (CDQ) and isorhamnetin 3-O-β-d-glucopyranoside (IDG), from Salicornia herbacea against COX-2 using both computational and in vitro approaches.MethodsComputational analysis, including molecular docking, molecular dynamics (MD) simulations, and post-simulations analysis, were employed to estimate the binding affinity and stability of CDQ and IDG in the catalytic pocket of COX-2 against Celecoxib as positive control. These predictions were further evaluated using in vitro enzyme inhibition as well as gene expression mediation in macrophages cells.ResultsMolecular docking analysis revealed substantial binding energy of CDQ (-6.1 kcal/mol) and IDG (-5.9 kcal/mol) with COX-2, which are lower than Celecoxib (-8.1 kcal/mol). MD simulations (100 ns) and post simulation analysis exhibited the substantial stability and binding affinity of docked CDQ and IDG compounds with COX-2. In vitro assays indicated significant COX-2 inhibition by CDQ (IC50 = 76.91 ± 2.33 μM) and IDG (IC50 = 126.06 ± 9.44 μM). This result supported the inhibitory potential of isolated bioactive compounds against COX-2. Also, a cellular level study revealed a downregulation of COX-2 expression in tumor necrosis factor-alpha stimulated RAW 264.7 macrophages treated with CDQ and IDG.ConclusionComputational and experimental analysis of CDQ and IDG from S. herbacea established their potential in the inhibition and mediation of COX-2. Hence, CDQ and IDG can be considered for therapeutic development against COX-2 linked disorders, such as inflammation and cancer. Furthermore, CDQ and IDG structures can be served as a lead compound for the development of advanced novel anti-inflammatory drugs. 相似文献
Wee1-like protein kinase (Wee1) is a tyrosine kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Based on a series of signaling pathways initiated by Wee1, Wee1 has been recognized as a potential target for cancer therapy. To discover potent Wee1 inhibitors with novel scaffolds, ligand-based pharmacophore model has been built based on 101 known Wee1 inhibitors. Then the best pharmacophore model, AADRRR.340, with good partial least square (PLS) statistics (R2?=?0.9212, Q2?=?0.7457), was selected and validated. The validated model was used as a three-dimensional (3D) search query for databases virtual screening. The filtered molecules were further analyzed and refined by Lipinski’s rule of 5, multiple docking procedures (high throughput virtual screening (HTVS), standard precision (SP), genetic optimization for ligand docking (GOLD), extra precision (XP), and unique quantum polarized ligand docking (QPLD)); absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening; and the Prime/molecular mechanics generalized born surface area (MM-GBSA) method binding free energy calculations. Eight leads were identified as potential Wee1 inhibitors, and a 50?ns molecular dynamics (MD) simulation was carried out for top four inhibitors to predict the stability of ligand–protein complex. Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) based on MD simulation and the energy contribution per residue to the binding energy were calculated. In the end, three hits with good stabilization and affinity to protein were identified.
Matrix metalloproteinase-9 (MMP-9) has been considered as an attractive target involving cancer therapy. In this study, the 3D QSAR pharmacophore model of MMP-9 inhibitors is built, and its reliability is subsequently validated based on different methods. The built pharmacophore model consists of the four chemical features, including two hydrogen bond acceptors (HBA), one hydrophobic (HY), and one ring aromatic (RA). Among them, both HY and RA are found to be especially important features because they involve the interactions of inhibitors with the S1′ pocket of MMP-9, which determines the selectivity of MMP-9 inhibitors. By combining pharmacophore model with molecular docking, the virtual screening is carried out to identify the selective MMP-9 inhibitors from natural products. The four potential selective MMP-9 inhibitors of natural products are found. One of them was used to carry out the bioassay experiment inhibiting MMP-9, and the estimated IC50 value of only 26.94 µM clearly shows its strongly inhibitory activity; besides, both the hybrid quantum mechanics/molecular mechanics (QM/MM) calculation and the molecular dynamics simulation are performed to examine the reliability regarding the binding mode of this inhibitor with MMP-9 active sites predicted by molecular docking. All the screened four natural products are found to well bind with the MMP-9 active sites by different kinds of interactions. Finally, the ADMET properties of screened four natural products are assessed. These screened MMP-9 inhibitors of natural products could be used as the lead compounds to perform structural modifications and optimizations in the future work.
