In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity (original) (raw)
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International Journal of Advances in Engineering and Pure Sciences, 2021
Inflammations generate uneasiness. This study adopts quantum mechanical and molecular docking approach to model and explore twenty derivatives of ibuprofen as potential non-steroidal anti-inflammatory drug candidates taking ibuprofen as the standard. Optimization and calculation of the drug-like quantum chemical parameters of the compounds were conducted at DFT/B3LYP/6-31G* level of theory. Binding affinity, interaction and inhibition of the potential drug-candidates with human COX-2 receptor were investigated using molecular docking studies. Pharmacokinetic properties were studied. The drug candidates interact effectively and spontaneously with the COX-2 receptor via hydrogen bonding and π-π stacking with great binding affinity. The energy gap, global hardness and softness, and chemical potential of the derivatives suggest that they are kinetically unstable, more chemically reactive than the parent drug and are effective electron donors. From the pharmacokinetic studies, all the de...
In Silico Analysis of Inhibitors for Inflammatory Targets
Human Inflammation is a complex biological response of tissues caused by pathogens, irritants, or damaged cells called as harmful stimuli. Immunological response by the organism towards the injurious stimuli is inflammation. Healing process of the tissues is initiated by this mechanism. Absence of inflammation leads to host of diseases such as fever, atherosclerosis and rheumatoid arthritis. For this reason inflammation is normally closely regulated by the body. The phenothiazine nucleus is well known for its inhibitory activity towards the regulatory enzymes that contribute to inflammatory diseases. Phenothiazines biological activity against the regulatory enzymes like phosphodiesterase (PDE), prostaglandin dehydrogenase (PS) and superoxide dismutase (SOD) control the inflammation. In the present study, analogues of phenothiazines were used for molecular docking. Inhibitors, which are having good inhibitory activity against the targets, were taken from the literature. Sixteen inhibitors of phenothiazine and their IC50 values were taken from literature. The proteins and ligands were energy minimized using OPLS force field. High throughput Virtual Screening had been carried out for all these compounds and based upon their glide energy, glide score and their IC50 values, some of the ligands were selected for Induced fit docking studies. The result shows that some of the ligands maintain favourable interactions with the active site residues of the target molecule. All docking studies were performed using the molecular modelling software GLIDE of Schrodinger package.
International Journal of Pharma Sciences and Research
Introduction The Covid 19 pandemic has put the cardiovascular risk incurred when using nonsteroidal anti-inflammatory drugs at the heart of the discussion. Based on the information currently available, WHO does not recommend the use of ibuprofen. the objective is to evaluate the inhibition of cyclo-oxygenase 2 by ibuprofen by validating molecular docking. Method The crystallographic structure of ibuprofen bound to cyclooxygenase-2 was obtained from the Protein Data Bank (PDB) at a resolution <3.00 Å. The receiver was visualized using Discovery Studio Visualizer version 2.5.5. It was efficiently prepared using AutoDock / Vina software. The 3D structure of Ligand (Ibuprofen) was downloaded from the Drugbak database (https://www.drugbank.ca/): Accession number DB01050 Results Molecular docking was chosen as the first-line discrimination of the ibuprofen-COX2 intercation for the in silico study of putative competitors. The complex formed by Ibuprofen-COX 2 from the experimental model...
Chemical Biology & Drug Design, 2018
The aim of this work was to compare the anti-inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen. The antiinflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of lipoxygenases (LOX) and COX-2, and in silico docking studies in 15-LOX and COX-2. The synthesized hybrids showed an inhibition of COX-2 and LOX between 9.8%-57.4% and 0.0%-97.7%, respectively. None of the hybrids showed an improvement in the inhibitory effect toward these pro-inflammatory enzymes, compared to the parent terpenes and non-steroidal anti-inflammatory drugs. The docking studies allowed us to predict the potential binding modes of hybrids 6-15 within COX-2 and 15-LOX active sites. The relative affinity of the compounds inside the binding sites could be explained by forming non-covalent interactions with most important and known amino acids reported for those enzymes. A good correlation (r 2 = 0.745) between docking energies and inhibition percentages against COX-2 was found. The high inhibition obtained for compound 10 against COX-2 was explained by hydrogen bond interactions at the enzyme binding site. New synthetic possibilities could be obtained from our in silico models, improving the potency of these hybrid compounds. K E Y W O R D S anti-inflammatory activity, computational analysis, COX-2 and 15-LOX inhibition, ibuprofen and naproxen terpenyl hybrids, in silico studies
Current Drug Discovery Technologies, 2016
Prompted by the ineptness of the currently used non-steroidal antiinflammatory drugs (NSAIDs) to control gastric mucosal and renal adverse reactions, several ester prodrugs of ketoprofen were synthesized and characterized by IR, 1 H NMR and mass spectral data. Physicochemical properties such as aqueous solubility, octanol-water partition coefficient log P, chemical stability and enzymatic hydrolysis of the synthesized molecules have been studied to assess their potential as prodrugs. The obtained results confirmed that all ester prodrugs are chemically stable, possess increased lipophilicity compared to their parent compounds and converted to the active drugs in vivo. All of the tested ester prodrugs exhibited marked anti-inflammatory activity ranging from 91.8% to 113.3% in comparison with the parent drug, ketoprofen. A mutual prodrug obtained from two antiinflammatory molecules, ketoprofen and salicylic acid has been noted to potentiate the activity making it most active molecule of the series. The ulcerogenic index of the ester prodrugs was significantly lower than the parent drug, ketoprofen. Comparative docking studies against X-ray crystal structures of COX-1 and COX-2 further provided understanding of their interaction with the cyclooxygenases that will facilitate design of better inhibitors (or prodrugs) with sufficient specificity for COX-2 against COX-1. The study offers an innovative strategy for finding a molecule with safer therapeutic profile for longterm treatment of inflammatory diseases.
Molecules
A novel derivative of ibuprofen and salicylaldehyde N′-(4-hydroxybenzylidene)-2-(4-isobutylphenyl) propane hydrazide (HL) was synthesized, followed by its complexation with Cu, Ni, Co, Gd, and Sm. The compounds obtained were characterized by 1HNMR, mass spectrometry, UV-Vis spectroscopy, FT-IR spectroscopy, thermal analysis (DTA and TGA), conductivity measurements, and magnetic susceptibility measurements. The results indicate that the complexes formed were [Cu(L)(H2O)]Cl·2H2O, [Ni(L)2], [Co(L)2]·H2O, [Gd(L)2(H2O)2](NO3)·2H2O and [Sm(L)2(H2O)2](NO3)·2H2O. The surface characteristics of the produced compounds were evaluated by DFT calculations using the MOE environment. The docking was performed against the COX2 targeting protein (PDB code: 5IKT Homo sapiens). The binding energies were −7.52, −9.41, −9.51, −8.09, −10.04, and −8.05 kcal/mol for HL and the Co, Ni, Cu, Sm, and Gd complexes, respectively, which suggests the enhancement of anti-inflammatory behaviors compared with the bin...
Asian Journal of Chemistry, 2018
Cyclooxygenase, commonly known as COX, converts arachidonic acid to prostaglandin. Arachidonic acid is formed in the process of lipid metabolism through the catalytic activity of lypooxygenase. COX, first converts arachidonic acid to prostaglandin-H2 (PGH2) and then to various other prostanoids like PGE2, PGD2, PGF2α, PGI2 as well as thromboxane TXA2 [1]. Prostaglandins are the effective mediators of inflammation and also produce hypersensitive life-threatening allergic reactions [2]. COX occurs in two different isoforms, namely COX-1 and COX-2. COX-2 has nearly 60 % homology with COX-1 in gene sequence. COX-1 is always present in most cells and performs protective housekeeping role in the production of prostanoids. One of the important functions of COX-1 is to protect and maintain gastrointestinal tract. COX-2 is generally induced by inflammatory stimuli and is responsible for nearly 20 times elevated production of prostaglandins [3]. The elevated production of prostaglandin is responsible for redness, heat, swelling and pain, all associated with inflammation. Nonsteroidal anti-inflammatory drugs (NSAID) efficiently inhibit COX-2 and are commonly used during fever and pain. These
Biological Evaluation and Molecular Docking Studies of Benzalkonium Ibuprofenate
Computational Biology and Chemistry [Working Title]
The third-generation ionic liquids (ILs), which are being used to produce double active pharmaceutical ingredients (d-APIs) with tunable biological activity along with novel performance, enhancement, and delivery options, have been revolutionizing the area of drug discovery since the past few decades. Herein we report the in vitro antibacterial and anti-inflammatory activity of benzalkonium ibuprofenate (BaIb) that are being used as in-house d-API, with a particular focus on its interaction with respective protein target through molecular docking study. The evaluation of the biological activity of BaIb with the antibacterial and anti-inflammatory target at the molecular level revealed that the synthesized BaIb could be designed as a potential double active drug since it retains the antibacterial and anti-inflammatory activity of its parent drugs, benzalkonium chloride (BaCl) and sodium ibuprofenate (NaIb), respectively.
Computer aided discovery of potential anti-inflammatory (S)-naproxen analogs as COX-2 inhibitors
Medicinal chemistry (Shāriqah (United Arab Emirates)), 2013
A series of substituted 2-(6-methoxynapthalen-2-yl) propanoic acid (naproxen) analogs were synthesized. (S)- naproxen (1) was treated with thionyl chloride to yield acid chloride (2) which was then reacted with different heterocyclic moieties and aryl acids to yield the (S)-naproxen analogs (3a-k). All the compounds were screened for antiinflammatory activity using in vivo rat paw oedema model and most of the active ones were investigated for their ulcerogenic potential. In silico studies (molecular modeling and docking) were carried out to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzymes (COX-1 and COX-2) employing Maestro (Version 9.1, Schrodinger, LLC.) software. 2-(1-(2(2-methoxynaphthalen-6-yl)propanoyl)-1H-indol-2-yl) acetic acid (3k) was found to be the most active compound amongst the series with inhibition of paw edema volume by 62.1%, in silico sitemap score of -0.40kcal/mol and ulcerogenic index as least as 1.19.
PLOS ONE, 2015
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.