Molecular Operating Environment Program Research Articles

In silico study of five new sulfonamide derivatives bearing a thiazolidine-4-one moiety: targeting carbonic anhydrase IX

Molecular docking simulations were utilized to determine the binding affinities of five compounds produced. These compounds were IVa, IVb, IVc, IVd, and IVe. Chemicals derived from thiazolidin-4-one were designed to target cancer and human carbonic anhydrase IX (PDB code: 4M2V). These chemicals were designed to target humans. Our de¬tailed sketching of the structure of the molecules was accomplished with the help of Chem Draw Ultra 12.0. To validate the compounds produced, the S. score and Rmsd values of the compounds were examined using the Molecular Operating Environment program. In contrast to acetazolamide, the proteins of the synthesized compounds had con¬siderable binding affinities with the receptor active pocket, which suggested potential activity against cancer.

Computer screening of peptidomimetics and small-molecule ligands of B-cell membrane proteins for therapy of Burkitt lymphoma

The capabilities of molecular modelling and docking allow for the discovery of new potential drug agents to improve the treatment of diseases, which is a current concern. The objective of this study was to conduct in silico screening for antibody mimetics to B-cell membrane proteins for the treatment of Burkitt lymphoma through virtual screening. In this work, a standard protocol for structure-based virtual screening was employed, with the distinction that pharmacophores for screening were built not based on small-molecule ligands but on selected amino acid residues of antibodies. Based on literature data and the presence of a mechanism of direct cytotoxic action, as well as the availability of 3D structures of complexes, three monoclonal antibodies were selected: obinutuzumab, epratuzumab, and atezolizumab. The identification of biological targets was carried out by searching for 3D structures of selected complexes with target proteins in the Protein Data Bank. For virtual screening, the web service Pharmit was chosen. Using the Molecular Operating Environment program, pharmacophore models were constructed for three complexes: CD20 and obinutuzumab, CD22 and epratuzumab, and PD-L1 and atezolizumab. Docking with the CD20, CD22, and PD-L1 proteins was conducted at the binding sites recognised by the original antibody. Through in silico virtual screening using the Molecular Operating Environment software, a search for antibody mimetics to B-cell membrane proteins for Burkitt lymphoma treatment was conducted, resulting in the selection of 5 potential anti-lymphoma agents: CHEMBL505179 for the CD20 receptor, an antagonist of the melanocortin receptor for CD20 (PubChem-44406884), an inhibitor of blood clotting Factor Xa for CD22 (PubChem-136510605), and a blocker of epithelial Na+ channels for CD22 (PubChem-126761430), and an agonist of the melanocortin receptor for PD-L1 (PubChem-25078192). The obtained results can be applied in the pharmaceutical industry and oncological practice to enhance therapeutic outcomes in the treatment of patients with Burkitt lymphoma

QSAR modeling, molecular docking and molecular dynamic simulation of phosphorus-substituted quinoline derivatives as topoisomerase I inhibitors

As they facilitate the cleavage of single and double stranded DNA to relax supercoils, unwind catenanes, and condense chromosomes in eukaryotic cells, Topoisomerase plays crucial roles in cellular reproduction and DNA organization. Because the unrepaired single and double stranded DNA breaks these complexes generate might result in apoptosis and cell death, they are cytotoxic agents.In this study, 28 compounds derived from phosphorus-substituted quinoline are subjected to a quantitative structure–activity relationship (QSAR) using partial least squares, principal component regression, and multiple linear regression. The Gaussian 09 software and the Molecular Operating Environment program were used to calculate molecular descriptors. The anti-proliferative activity was correlated with a variety of electronic and structural characteristics of the molecules, such as EHOMO (energy of the highest occupied molecular orbital) and ELUMO (energy of the lowest unoccupied molecular orbital), which provided evidence for the modeling. The B3LYP/6-31G (d, p) level of theory's Density Functional Theory (DFT) approach was used to compute these electronic properties, and Principal Component Analysis (PCA) was used to test for collinearity between the descriptors. In fact, three alternative prediction models were created using various 2D and 3D descriptor counts, and they were each assessed using the statistical metrics of coefficient of determination (R2) and root mean squared error (RMSE). A MLR model had the best predictive performance of all the constructed models, as indicated by R2 and RMSE of 0.865 and 0.316, respectively.Three proteins (6G77, 2NS2, and 5K47) for lung, ovarian, and kidney malignancies showed strong binding affinities via hydrophobic interactions and H-bonds with the pertinent chemicals by crystal structure modeling. Compounds C11, C19 and C26, respectively, showed the highest binding energy for ovarian, kidney and lung cancer. The outcomes of the molecular dynamic MD simulation diagram were produced to support the molecular docking findings from earlier research, which demonstrated thatinhibitors were stable in the active sites of the selectedproteins for 10 ns. This raises the possibility that these chemicals could serve as a valuable model for the development and synthesis of more effective anticancer prospects.

Design, synthesis, in silico study and preliminary pharmacological assessment of new gatifloxacin analogues having thiazole nucleus

Series of gatifloxacin derivatives (IVa-IVd) were synthesized by incorporation of thiazole ring (Which has antibacterial activity) and some of its derivatives into a secondary amine of piperazine ring at C-7 position of gatifloxacin nucleus, in order to increase bulkiness at this position by that reduce the affinity toward the efflux pump of bacterial cells, leading to reduction in bacterial resistance. By using FT-IR spectroscopy, 1H-NMR spectral and some of the physicochemical properties, the synthesized compounds were confirmed and characterized for their chemical structures. In-vitro study was performed to evaluate the antibacterial effect of all synthesized compounds and was revaluated by using agar- well diffusion method (AWD). The antibacterial study was shown a topmost inhibition zone for the compounds IVa and IVb against Staphylococcus aureus and the lowest inhibition zone for the two compounds IVc and IVd against E. coli. In silico study was performed using Molecular Operating Environment program and showed that all synthesized compounds were give affinity toward topoisomerase enzyme and these studies were compatible with the in vitro studies, as the compound IVb give the highest S score value.

Therapeutical Potential of Imines; Synthesis, Single Crystal Structure, Computational, Molecular Modeling, and ADMET Evaluation.

Imines are multipurpose pharmacophores, simply accessible compounds, and have a broad range of usage in several areas of chemistry especially in medicine. Two novel compound imines, (E)-4-methyl-2-((o-tolylimino)methyl)phenol (1) and (E)-2-(((4-methoxybenzyl)imino)methyl)-4-methylphenol (2), were synthesized with effective product via reported protocol in the literature. Single crystal X-ray diffraction (SCXRD) was employed for structural exposition, disclosing that both compounds are orthorhombic. To optimize the newly designed imines, a B3LYP functional with a basis set 6-31G(d,p) was mainly considered. DFT results were utilized to check correlation between the data recovered from SCXRD outcomes and also to measure the energy difference. Hirshfeld surface study was done to demonstrate the intermolecular contacts along the percentage of interaction in the overall crystalline compound. Molecular operating environment program was tested against AChE and BChE enzymes to perform a modeling study of the compounds. The docking score and binding affinity of the compounds revealed that 2 showed comparatively more inhibition than 1. In silico ADMET studies exposed the physiochemical nature of these novel compounds, and it also unveiled that both compounds behaved as drug-like candidates.

Exploration of aurora B and cyclin-dependent kinase 4 inhibitors isolated from Scorzonera tortuosissima boiss. and their docking studies

Background: Flavonoids are components of the daily human diet (fruits and vegetables), and it has been shown to inhibit several kinase enzymes. Due to its kinase inhibitory activity, they are expected to be of great importance in the discovery of new anticancer drugs. Objectives: The objective was to study the cytotoxicity, kinase inhibitory activity, and docking of the isolated aglycones. Materials and Methods: Ultraviolet, high-performance liquid chromatography (LC), nuclear magnetic resonance, and LC-mass spectrometry were used for the identification of the isolated metabolites. Antiproliferative (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) and radiometric protein kinase (PK) assays were used to measure the cytotoxicity and PK inhibitory effect of the isolated flavonoids. The docking study on both Aurora B and cyclin-dependent kinase 4 (CDK4)/CycD1 was performed by molecular operating environment (MOE). Results: Luteolin (1), quercetin (2), myricetin (3), apigenin-7-O -β-D-glucopyranoside (4), and kaempferol-7-O -β-D-glucopyranoside (5) were isolated from Scorzonera tortuosissima . Quercetin and myricetin exhibited the highest cytotoxicity against the Michigan Cancer Foundation-7 (MCF-7) (IC50: 5.56 and 7.14 μM, respectively) and against human hepatocellular carcinoma (HepG2) (IC50: 8.61 and 10.31 μM, respectively), while compounds luteolin and apigenin-7-O-β-D-glucopyranoside showed the least cytotoxicity compared to doxorubicin against to MCF-7 and HepG2 (IC50: 2.24 ± 0.85 and 1.82 ± 0.34 μM, respectively). The radiometric PK assay was applied for measurement of kinase inhibitory activity against Aurora B, CDK4/D1, cancer Osaka thyroid, IGF1-R, and FAK kinases, where the aglycone myricetin showed the highest inhibitory activity against Aurora B (IC50: 2.82 μM) and against CDK4/cyclin D1 (IC50: 3.16 μM), while the isolated glycosides 4 and 5 revealed the lowest activity. Docking of the most active compounds 1, 2, and 3 against Aurora B and CDK4/cyclin D1 confirmed its cytotoxic profile. Conclusion: The isolated flavonoids were firstly isolated from S. tortuosissima . The hypothetical mechanism of cytotoxic activity of 1, 2, and 3 on Aurora B and CDK4/cyclin D1 kinases was estimated by in silico study with these enzymes using MOE program.

Molecular Docking Studies of a Chalcone Derivative Compound p-hydroxy-m-methoxychalcone with Tyrosine Kinase Receptors

Chalcone compounds have been studied as therapeutic, especially as antitumor drugs. A chalcone derivate, para-hydroxy-metha-methoxychalcone (pHmMC) or 3-(4’-hydroxy-3’-methoxyphenyl)-1-phenyl-2propene-1-on, has been studied to explore its potential utilization as chemoprevention in several cancers cell lines. The main objective of the present work is to perform a docking analysis of pHmMC with tyrosine kinase receptors EGFR, HER2, and VEGFR comparing with ligand ATP. Docking studies were performed using PLANTS (Protein Ligand ANT System) software, while the preparations of protein and reference ligand was used YASARA, and visualizing amino acids was used Molecular Operating Environment (MOE) program. The docking studies indicated that the binding energy of pHmMC with EGFR (1XKK) and HER2 (3PPO) was higher than the ATP binding energy with the EGFR and HER2. However, the binding energy of pHmMC with VEGFR (2P2I) almost had the same energy binding compared with the ATP binding on VEGFR. VEGF is a protein that plays a role in angiogenesis. Data from the MOE program showed there were similarities in the amino acids involved in the interaction between pHmMC and ATP in binding to EGFR, HER2, and VEGFR. The results indicated that pHmMC has the potential to be developed as an anticancer which might through the mechanism of inhibiting the process of angiogenesis.

Synthesis and Evaluation of 5-Benzyl-1,3,4-Thiadiazole Derivatives as Acetylcholinesterase Inhibitors

Three novel 5-benzyl-1,3,4-thiadiazole derivatives were synthesised starting from phenylacetic acid derivatives. These compounds were characterised by NMR, HRMS and single-crystal X-ray diffraction analysis. 2-Pyrrolidyl-5-[2-(4-bromophenyl)methyl]-1,3,4-thiadiazole showed moderate acetylcholinesterase-inhibition activity with a 50% inhibitory concentration value of 33.16 μM. 2-Pyrrolidyl-5-[2-(4-bromophenyl)methyl]-1,3,4-thiadiazole and acetylcholinesterase docking was demonstrated using the Molecular Operating Environment program.

Three-dimensional quantitative structure–activity relationship analyses of substrates of the human proton-coupled amino acid transporter 1 (hPAT1)

The proton-coupled amino acid transporter hPAT1 has recently gained much interest due to its ability to transport small drugs thereby allowing their oral administration. A three-dimensional quantitative structure–activity relationship (3D QSAR) study has been performed on its natural and synthetic substrates employing comparative molecular similarity indices analysis (CoMSIA) to investigate the structural requirements for substrates and to derive a predictive model that may be used for the design of new prodrugs. The cross-validated CoMSIA models have been derived from a training set of 40 compounds and the predictive ability of the resulting models has been evaluated against a test set of 10 compounds. Despite the relatively narrow range of binding affinities (Ki values) reliable statistical models with good predictive power have been obtained. The best CoMSIA model in terms of a proper balance of all statistical terms and the overall contribution of individual properties has been obtained by considering steric, hydrophobic, hydrogen bond donor and acceptor descriptors (qcv2=0.683, r2=0.958 and rPRED2=0.666). The 3D QSAR model provides insight in the interactions between substrates and hPAT1 on the molecular level and allows the prediction of affinity constants of new compounds. A pharmacophore model has been generated from the training set by means of the MOE (molecular operating environment) program. This model has been used as a query for virtual screening to retrieve potential new substrates from the small-molecule, ‘lead-like’ databases of MOE. The affinities of the compounds were predicted and 11 compounds were identified as possible high-affinity substrates. Two selected compounds strongly inhibited the hPAT mediated l-[3H]proline uptake into Caco-2 cells constitutively expressing the transport protein.