جستجوی مقالات مرتبط با کلیدواژه "docking" در نشریات گروه "شیمی"

Mutations in FLT3 prompt hyperactivation of RAS/RAF/MEK/ERK growth signalling. The FLT3-D835Y mutation confers resistance to FLT3 inhibitors for acute myeloid leukemia (AML) therapy. The KRAS-G12C and BRAF-V600E are frequent mutations in several cancers. While inhibitors against RAS, RAF, MEK, and ERK are available, they are often unsuccessful against BRAF or KRAS mutations with reported toxicity rates. This study evaluates the potential of thymoquinone (TQ), a phytochemical obtained from Nigella sativa seed, to function as an inhibitor of FLT3-D835Y, KRAS-G12C, BRAF-V600E, MEK, and ERK and to modify the expressions of genes related to RAS/RAF/MEK/ERK signaling in MV4-11 AML cells. The cells were incubated with TQ and we utilized RT-qPCR to measure the target genes’ mRNA levels. Molecular docking of TQ and reference inhibitors to FLT3-D835Y, KRAS-G12C, BRAF-V600E, MEK, and ERK proteins was examined with calculations of binding energies. TQ produced significantly downregulated K-RAS, B-RAF, MEK1, and ERK2 expressions. TQ also docked to FLT3-D835Y, KRAS-G12C, BRAF-V600E, MEK1, and ERK2 with high binding affinities and low docking scores. The study identifies TQ as an inhibitor of multiple target mutations that could combat resistance to FLT3-D835Y, KRAS-G12C, and BRAF-V600E inhibitors, aiding in the improvement of AML therapy.

In this research, novel complexes of Zn(II) were produced using amino acid Schiff bases. First, new Schiff bases were synthesized from the reaction of 3-methoxy-2-hydroxybenzaldehyde (o-vanillin) and amino acid methyl esters (isoleucine, phenylalanine, methionine). The synthesis of new complexes was carried out by the reaction of these Schiff bases and Zn(OAc)2.2H2O. The structures of the synthesized complexes were elucidated using elemental analysis, FT-IR, NMR, UV-vis spectroscopy, and thermal analysis techniques. In this research, we synthesized new complexes of Zn(II) with amino acid Schiff bases labeled as 1a-1c. We then examined their impact on specific metabolic enzymes, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results showed that the molecules exhibited potent inhibitory activities against all targets compared to the standard inhibitor as indicated by IC50 values. Ki values of the compounds for AChE and BChE enzymes were obtained in the range of 78.04±8.66-111.24±12.61 and 24.31±3.98-85.18±7.05 µM, respectively. Molecular docking calculations were performed to investigate the biological activities of the metal complexes. The Protein Ligand Interaction Profiler (PLIP) was used to study the chemical interactions of metal complexes with enzymes.

CP47 is one of the essential components of photosystem II (PSII) in green plants, green algae, and cyanobacteria; which is involved in the light reactions of photosynthesis. Various studies have shown that the binding of the extrinsic protein of 33 kDa (PsbO) to the large extrinsic loop of CP47 (E loop) is an essential photoautotrophic activity of the PSII complex. Moreover, the deletion of the amino acids between Gly-351 and Thr-365 within loop E failed to assemble stable PSII centers. In this study, using computational methods, the effect of Phenylalanine (Phe) mutation at position 363 on Synechocystis sp. PCC 6803 CP47 was investigated and then the mutant model was compared with the native one. Because the experimental 3D structure of Synechocystis sp. PCC 6803 CP47 and PsbO proteins are not available in the Protein Data Bank (PDB), the 3D structure of these proteins was modeled by homology modeling. After refining and energy minimization, the quality of protein geometry was assessed by different criteria such as PROCHECK and ProSA. Then, structural analysis of mutant and native models was performed with Molecular Dynamic (MD) simulation and docking method. The analysis of results obtained from MD simulation shows that F363R mutation affects the flexibility of some regions and especially leads to an increase in mutation region and changes the conformation of CP47. In addition, the results of docking studies indicate that F363R mutation can decrease buried surface area (BSA) at the interface region and decrease the binding energy of CP47 and PsbO. These data reinforce our hypothesis that an increase of flexibility at the position of F363 in the large extrinsic loop of CP47 may be an important factor in reducing interaction between CP47 and PsbO extrinsic protein and then water oxidation. oxidation.

The novel 2-[(E)-(3-phenylmethoxyphenyl)methylideneamin-o]guanidine was put forth as a potential anti-SARS-coronavirus-2 candidate targeting the spike glycoprotein following a docking simulation study. When compared with the standard medications (Chloroquine and Ruxolitinib) with a binding score of -4.8 kcal/mol and -7.0 kcal/mol, respectively, 2-[(E)-(3-phenylmethoxyphenyl) methylideneamino] guanidine's computed binding score of -7.2 kcal/mol indicated that it may have promising anti-SARS-coronavirus-2 activity. The accurate binding of 2-[(E)-(3-phenylmethoxyphenyl) methylideneamino] guanidine to the SARS-coronavirus-2 spike glycoprotein through the appropriate dynamic and energetic behaviours over 20 ns was verified by molecular dynamics simulations as well as MM/GBSA studies. Besides that, in silico ADME studies demonstrated 2-[(E)-(3-phenylmethoxyphenyl) methylidene-amino]guanidine's general safety and drug-likeness. As a result, the outcomes of this survey gave a strong basis for the in silico plan and hypothetical investigation of more potent SARS-coronavirus-2 inhibitors.

A new series of 3-furan-2-yl-1-p-aryl-propenone derivatives containing imine moieties (1-7) were synthesized and characterized using spectral analysis. The synthesized derivatives were screened in vitro against several bacterial species, including Acinetobacter baumannii, Klebsiella pneumonia, Pseudomonas aeruginosa (Gram-negative bacteria), and Staphylococcus aureus (Gram-positive bacteria) to study the effect of different imine moieties on the activity of (E)-1-(4-aminophenyl)-3-(furan-2-yl)prop-2-en-1-one, which represent the potent hit against different bacterial species. The synthesized compounds were found to exhibit modest to vigorous activity, especially compounds 1, 4, and 6-7. The minimum inhibitory concentrations (MICs) of compound 1 and 6 against Acinetobacter baumannii and Staphylococcus aureus were determined. The anti-biofilm activity of the potent discovered compounds (1, 4, 6, and 7) against Acinetobacter baumannii and Staphylococcus aureus were also determined. Docking study of the best discovered hits against the active site of glucosamine-6-phosphate synthase, the antimicrobial target enzyme was achieved to explore the interactions of the synthesized hits inside the enzyme residues.

The N3 tridentate ligand N,N-dimethyl-N-(1-pyridinylmethylidene) propane-1,3- diamine (DPMPD) and its copper complex (CDPMPD) were synthesized of which metal complex is found  in green colour  powdered form. The associated spectroscopic techniques were used to characterize both ligand and the metal complex. Powder XRD method was utilized using the Scherrer formula to accomplish the grain size of the metal complex. It was found that the experimental results of the powdered complex were quite similar to that of the reference material with JCPDS ID 00- 024-1977. In vitro anticancer activity shows that the metal complex exhibits a moderate cytotoxic effect on Hep-G2 cell line. This cytotoxic phenomenon is well supported by a molecular docking study using target topoisomerase II crystal structure (PDB id 4FM9). The HOMO- LUMO energy gap, predicted from the DFT study, signifies that the complex is susceptible to chemically reactive.

T. callosum an endemic plant, used in this study, efficiently inhibited enzymes, with IC50 values of 28.87 mg/mL, 15.75 mg/mL, 36.47 mg/mL, and 60.0 mg/mL, for AChE, BChE, α-Gly, and GST respectively. The antioxidant activities of the water and methanol extracts of T. callosum were investigated using four in vitro techniques. The antioxidant activity of water extract against ABTS radical was very strong as in the case of standards. Rosmarinic acid (2080.4 µg /g), quercetin-3-D-glycoside (853.8 µg /g), and shikimic acid (784.8 µg /g) were detected as the most intensive phenolic compound in T. Callosum by using the advanced LC-MS/MS technique. The computational screening of the studied ligands revealed the docking energies in the range of -4.217to -9.027kcal/mol for used enzymes. Rosmarinic acid and quercetin 3-O-glucoside showed binding energies of < -8 kcal/mol with AchE and BChE respectively. In conclusion, the biological activities of the plant might be due to its rich chemical composition.

Uricase is widely used to treat hyperuricemia and gout. Its clinical use is complicated by patients severe allergy, hypersensitivity and anaphylactic reactions. Uricase from Arthrobacter globiformis (Ag) and Bacillus fastidious (Bf) was chosen to improve enzyme binding energy by reducing the deleterious effects in treatment. Reducing the adverse effects of uricase was achieved by in silico mutagenesis. Pymol altered the active site amino acids of uricase from both sources.The ligand uric acid was docked to mutated uricase by Autodock 4.0, which helps in improving uricase binding energy. It has been found that mutation of Val64 with Alanine in Ag uricase and Gly42 with Isoleucine in Bf uricase improved the binding energy ability of enzyme by 50%. The binding affinity of Ag uricase docked with uric acid was found to be -8.414 Kcal/mole while for the mutated protein it was found to be -8.570 Kcal/mole. Binding energies for Bf uricase were found to be -5.221, and 5.389 Kcal/mole for native and mutated protein. We infer that our In silico model with improved uricase binding energy can assist to make a potent drug by the help of protein mutagenesis which leads to develop a drug with minimum adverse effects to treat hyperuricemia.

Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR) as appropriate targets for cancer therapy have recently made a noteworthy field since the introduction of vandetanib as a dual inhibitor of VEGFR and EGFR tyrosine kinases (TKIs). In this study, twelve quinazoline derivatives were designed, synthesized, and evaluated for their cytotoxicity on A431 (human carcinoma cell) as well as HU02 (Foreskin fibroblast) cell lines by MTT assay. The binding mode of the most potent compound (8a) with EGFR and VEGFR2 was studied using molecular docking. Most of the compounds showed significant inhibition on the growth of A431 cells at the concentration lower than 100 µM. The compound 8a bearing diethylamine along with 4-bromo-2-fluoroaniline exhibited the best cytotoxic activity (IC50=2.62 μM) compared to erlotinib and vandetanib as positive controls. Synthesized compounds did not indicate significant cytotoxicity against HU02 cell line. The compound 8a indicated binding energies of -6.39 and -8.24 kcal/mol as well as inhibition constants of 20.67µM and 0.9µM with EGFR and VEGFR-2, respectively, which showed the effective binding with VEGFR-2.  The higher potency of 8a may be put down to the flexibility of diethylamine and its higher lipophilicity as well as lower steric hindrance of this substituent.

Phytosterols derived from medicinal plants are well-known for their therapeutic effects in the treatment of diabetes, cardiovascular disease, cancer, and microbial infections. Strychnos innocua (a Loganiaceae family member) grows in numerous African countries and is widely used for medicinal purposes. This plant's (root bark) ethyl acetate extract was subjected to chromatographic separation, resulting in the isolation of Campesterol (1) and β-Sitosterol (2). Their structures were verified using mass spectrometry, nuclear magnetic resonance (1D and 2D NMR), and in comparison to published data. This is a novel report of phytosterol compounds which were isolated from S. innocua root bark. The in silico investigation found that the binding affinities of Campesterol (1) with binding sites of Staphylococcus aureus pyruvate carboxylase (PDB: 3HO8) and Pseudomonas aeruginosa virulence factor regulator (PDB: 2OZ6) were -7.8 and -7.9 kcal/mol, respectively. Furthermore, the binding affinities of β-Sitosterol (2) with binding sites of S. aureus and P. aeruginosa are -7.6 and -7.7 kcal/mol, respectively, while ciprofloxacin (standard drugs) exhibited binding affinities of -6.6 and -8.7 kcal/mol. This study concluded that the S. innocua root bark has a rich presence of Campesterol and β-Sitosterol, while their molecular docking studies revealed that they have excellent interactions with S. aureus and P. aeruginosa.

Terpenoids are definite secondary metabolites with active therapeutic components that contribute to plants’ medicinal potential. Strychnos innocua is a Loganiaceae family medicinal plant found in various African countries. This study reports the isolation, characterization, and molecular docking analyses of Linalool (1) and Nerolidol (2) from ethyl acetate root bark extract of S. innocua. Their structures were validated using mass spectrometry, nuclear magnetic resonance (1D and 2D NMR), and compared with literature data. This is a novel report of terpenoids isolated from S. innocua root bark. An in silico docking examination revealed the binding energies of Linalool with the binding sites of Staphylococcus aureus pyruvate carboxylase (PDB: 3HO8) and Pseudomonas aeruginosa virulence factor regulator (PDB: 2OZ6) were -4.7 and –5.6 kcal/mol, respectively. Furthermore, the binding energies of Nerolidol with the binding sites of S. aureus and P. aeruginosa were -5.8 and -6.9 kcal/mol, respectively. Compared to ciprofloxacin (standard drug), which showed binding energies of -6.6 and -8.7 kcal/mol, respectively. This study concluded that Linalool and Nerolidol are abundant in the root bark of S. innocua. At the same time, docking results revealed that the compounds had moderate interactions with S. aureus and P. aeruginosa, exhibiting antibacterial effects.

Dengue fever is the most common and important arthropod-borne viral illness in humans. However, no effective medications or vaccinations exist to prevent this condition. The dengue viral (DENV) protease non-structural protein (NS) 2B-3 is a possible target for antiviral treatment. Based on the lead compound reported in our earlier study, eight phthalazinone analogues were designed using a structure-based drug design approach, which involved systematic alterations to the various positions of the benzyl ring bearing carbamate pharmacophore and carbamate terminal chain length of the lead. These compounds were also evaluated for in silico ADME properties and drug-likeness. The molecular docking scores of the design ligands were greater than the template’s binding score, ranging from-8.9 to-9.60 kcal/mol, and also higher than those of the Ribavirin and the co-crystalized protease ligand, which were -8.90, -6.10, and -8.10 kcal/mol, respectively. All of the developed ligands satisfied Lipinski's requirements with good synthetic accessibility (3.07–3.41) and a better ADME profile than the template, indicating that they were highly bioavailable and simple to synthesize in the laboratory. Phthalazinone derivatives with higher binding scores (-9.0 to -9.60 kcal/mol) were designed and found to interact well with the DENV NS2B-NS3 protease. The compounds also have significantly improved pharmacokinetic and ADME properties compared to their parent template. The designed compounds could be used as a starting point for developing potent DENV NS2B-NS3 protease inhibitors with suitable pharmacokinetic and ADME properties.

The COVID-19 outbreak caused by the SARS-CoV-2 virus in late 2019 and early 2020 comprises a serious pandemic threat worldwide. Given the severity of the disease and the fact that there is no approved cure for this infectious disease, it seems reasonable to search for better candidates' drugs among approved antiviral or even antibacterial drugs for their anti-COVID-19 capability in contrast to the currently approved drugs. The enzyme main protease of SARS-CoV-2 that plays an important role in the virus life cycle seems to be a good target for inhibition by drugs. Accordingly, in the present work by using the molecular docking method we used the newly released coordinate structure of the protease as a target and 40 approved drugs from anti-viral, anti-parasite anti-malaria groups as ligands for docking experiments. Blind and active site-directed docking experiments were carried out on the optimized and equilibrated structure of protease at pH 7, 37 degrees centigrade of temperature, and 1 atmosphere of pressure. Our results indicate that based on binding energy, percent of binding site occupation, membrane transportability, and the maximum allowed dosage, erythromycin, clarithromycin, Amprenavir, Darunavir, Cefixime, and Tetracycline are among the enrolled drugs merit best parameters for clinical evaluation and their therapeutic potential in COVID-19 outbreak.

Inhibitory activities of five derivatives of 1,2,3-triazole and isoxazole-linked pyrazole hybrids (A,B,C,D and D) were investigated on two bacteria cell lines E.coli (5R1R) and S.aureous (2XCT) to predict their potency and their use as antibacterial agents. Spartan’14 was used to optimized the compounds via Density functional theory to calculate the molecular descriptors of the studied ligands and a standard drug (Amoxicillin). All the ligands obey Lipinski rule except ligand E with higher molecular weight greater than 500g/mol. The band gap which explained the stability of the ligand-protein complex formed were observed to be lower than the standard with outstanding lower band gap from Ligand B and E, hence this two ligand is expected to have higher stability as compared to other ligands and the standard drug. The predicted affinities via docking studies for E.coli were -7.3kcal/mol, -8.5kcal/mol, -7.5kcal/mol, -7.9kcal/mol, -8.9 kcal/mol and S.aureous were -6.9kcal/mol, -7.8kcal/mol, -7.0kcal/mol, -7.5kcal/mol. -7.3kcal/mol for Ligand A, B, C, D and E respectively. Also a standard drug (Amoxicillin) was also subjected to docking studies with the two receptor. However, the two ligands gave better inhibition at the active site of the two protein as compared to the standard drug with higher affinities from Ligand B, D and E. In addition, ADMET properties of the ligands displayed that all the ligands could be better absorbed from the intestinal tract when administered orally with no toxicity and they are not easily undergo biodegradation. Therefore, the ligands are good drug candidate which could be considered for clinical trials.

Rising cases of antibiotic-resistant bacteria is a public health concern. Many approved antibiotics target penicillin-binding proteins example peptidoglycan transpeptidase (PTPase). Due to wide pharmacological activity of phenothiazines, new styryl, aryl, alkynyl, and thiophenyl benzo[a]phenothiazines were synthesized and their inhibitory potency against PTPasein silico and Gram-positive/Gram-negative bacteria evaluated. The compounds inhibited the activity of PTPase at 18.93 - 75.48 µM and their best-docked poses identified interaction with PTPase Tyr318, His336, and His352. Experimental results agreed with computational predictions and further confirmed the benzo[a]phenothiazines as potential antibiotics. Also, the identified essential residues could be targeted during the rational optimization of the analogs.

AChE is an enzyme that is predominate in a healthy brain, while BChE is considered to play a minor role in regulating the levels of ACh (memory molecule) in the brain. In addition to setting the ACh level, these two enzymes also facilitate Aβ aggregation by forming stable complexes and participate in the abnormal phosphorylation of the tau protein, which also contribute to the development of Alzheimer’s disease (AD). Trace elements including Zn2+, Cu2+, and Fe2+ are found in the brain plaques of Alzheimer’s patients. This study employed tacrine as an efficient inhibitor of cholinesterase and quercetin as a natural metal chelating agent to design a new multi-target-directed ligand, which has been named Tac-Quer. The chelating properties of this ligand have been studied by quantum calculations. The Tac-Quer/Metal binding energies for Zn2+, Cu2+, and Fe2+ are -939. 08, -917.62, and - 694.103 kcal.mol-1, respectively. The cholinesterase enzyme inhibitory activity of the Tac-Quer ligand has been evaluated via molecular dynamic simulations. The free energies for the AChE/Tac-Quer and BChE/Tac-Quer complexes are -17.17 and -29.16 kcal.mol-1, respectively. Based on the results of this investigation, Tac-Quer is introduced as a potent multi-target-directed ligand that can be recognized as a promising treatment for AD.

Candida albicans is an opportunistic fungal pathogen that causes candidiasis in human hosts. Candidiasis includes a multitude of fungal infections, including invasive fungal infections, where most patients are immunocompromised; hence, the success of treatment is determined by the efficacy of the antifungal agent. However, with the increase in resistance to the existing drugs, the availability of effective antifungal agents is becoming scarce. Many pyrimidine derivatives exhibit powerful antifungal activity. In this study, In silico antifungal activity was carried out on twenty novel aminopyrimidine derivatives to identify the specificity of the pyrimidine analogues for the antifungal targets using ‘Glide’. Molecular docking studies were conducted on two antifungal targets; Dihydrofolate reductase of C. albicans (PDB ID: 4HOE); N-myristoyl transferase of C. albicans (PDB ID: 1IYK); energy minimization of title compounds was carried out using LigPrep, the protein targets were optimized and minimized, a 3-dimensional grid was generated at the active site, and molecular docking was carried out at both the standard precision (SP) and extra precision (XP) modes. The docking poses were ranked according to their docking scores (GScore) and their binding energy with the enzyme (Emodel). The obtained results for the docking of the title compounds with dihydrofolate reductase of C. albicans are quite promising. Molecular docking suggest that compounds 2N and 2A are potential inhibitors of  dihyfrofolate reductase and are specific in binding at the active site of the enzyme. They form pi-pi stacking interactions with PHE 36 at the active site of the protein, similar to the standard drug. However the test compounds show lower docking scores against N-myristoyl transferase of C. albicans indicating that they may not be effective against the fungal protein.

A simple method was developed to synthesize N-(3-(4-Chlorophenoxy)benzyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine by coupling 3-(4-Chlorophenoxy)phenyl)methanamine and 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine. The products have been obtained in good yields and were characterized by spectral analyses and finally, docking studies were carried out. the formula is not displayed correctly!

Human serum albumin (HSA) is one of the main endogenous vehicles for biodistribution of molecules by blood plasma. Association constants and thermodynamic parameters for the interaction of HSA with doxorubicin were studied by docking. Docking study suggests that doxorubicin is able to interact with HSA by means of hydrogen bond with one arginine residue, whereas the hydroxyl group is inserted in a hydrophobic pocket. The estimated of Gibbs free energies (ΔG°) is equal to -9.1 kcal/mol for the best model. The negative values of ΔG° indicate a spontaneous process. The association constant value (Ka ≈ 8×103 L.mol−1) is favorable for its efficient biodistribution by blood plasma.

Several compounds have been prepared to treatment of breast cancer; however, some of these drugs may produce some side effects. The aim of this study is to synthesize two new steroid derivatives (Compounds 7 or 8) to evaluate their theoretical interaction with a breast cancer protein (BRCA-1) using a docking model. The preparation of 7 and 8 was carried out using a series of reactions which involves; (i) addition/cyclization; (ii) amination, (iii) etherification and (iv) esterification. Chemical structure of the compounds was confirmed using elemental analysis and NMR spectrum. The following stage involved the theoretical evaluation on the interaction of both compounds 7 or 8 with BRCA-1 protein surface using a docking model. The results showed that compound 7 could bound to different type of amino acid residues of BRCA-1 protein compared with 8; this phenomenon, may exert changes in the biological activity of BRCA-1 protein. All data suggest that compound 7 or 8 could be an alternative therapeutic for treatment of the breast cancer.