Structural Modification of Ibuprofen as new NSAIDs via DFT, Molecular Docking and Pharmacokinetics Studies (original) (raw)
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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...
SN Applied Sciences
Paracetamol or acetaminophen is a medication commonly used in pain and fever. It is typically used for mild to moderate pain relief. It can produce selective inhibition to the prostaglandin synthesis. We envisage the density functional theory (DFT) with B3LYP/6-31G+(d,p) basis set to optimize the newly modified derivatives. Thermodynamic properties, molecular orbital features, dipole moment, atomic partial charge and electrostatic potential have been calculated in order to compare their physicochemical and biological properties. Molecular docking, nonbonding interactions, and dynamics simulation have been performed against prostaglandin H2 (PGH2) synthase protein 5F19 to investigate their binding affinity, binding modes, and stability of the protein-drug complex. ADMET prediction has been utilized to compare the absorption, metabolism, and carcinogenic properties of new derivatives with parent drug (PCT). From physicochemical data, all modified structures are thermodynamically stable; most of them are chemically more reactive and show better binding affinity than the parent drug. ADMET calculations predict the improved pharmacokinetic properties of modified derivatives. Based on physicochemical, docking, dynamics simulation and ADMET prediction results, this study can be helpful to design a new analgesic and antipyretic drug.
2015
Understanding the geometry, electronic properties of non-steroidal anti-inflammatory drugs (NSAIDs) and the nature of their interactions with human cyclooxygenase-2 (COX-2) is important in development and design of novel NSAIDs. In this paper, B3LYP/6-311++G (d,p) level of theory was applied to assess acidity of NSAIDs in the gas phase. Subsequently, the role of intramolecular hydrogen bond on acidity of these compounds was confirmed by means of natural bond orbital (NBO) and quantum theory of atoms in molecules analyses (QTAIM). Furthermore, by applying the polarized continuum model (PCM) at the B3LYP/6-311++G(d,p) level, the p K a value of NSAIDs in aqueous solution has been calculated. The maximum error was found to be less than 0.1 p K a unit in comparison with the experimental value. This protocol can be used as a tool to predict p K a values of NSAIDs in future studies. In the last step, attempts have been made to generate a functional model of the structure of human COX-2 enz...
Computational Biology and Chemistry, 2020
In this paper, theoretical study on molecular geometry, vibrational, pharmaceutical and electronic properties of the monomeric and dimeric structures of 1-benzothiophene-2-carboxylic acid (2BT) were carried out using B3LYP hybrid functional with 6-311++G(d,p) as basis set. The structural study show that the stability of 2BT crystalline structure arising from O-H…O, C-H…O as well as S-H…O hydrogen bonding interactions. Vibrational analysis, for monomer and dimer species, show a good compatibility between experimental and theoretical frequencies. Then, the 1H and 13C NMR chemical shifts were calculated using Gauge Independent Atomic Orbital (GIAO) technical. In addition, the UV-Vis spectrum was simulated in gas phase and in water throughout TD-DFT calculation. The electronic transitions were identified based on HOM-LUMO energies. However, donoracceptor interactions and charge delocalization has been studied via natural bond orbital (NBO). The nucleophilic and electrophilic site localization is identified by molecular electrostatic potential. Hirshfeld surface analysis has been discussed based on color code demonstrating the various non covalent interactions. Besides, molecular docking analysis was reported to evince the pharmaceutical properties of the studied molecule.
International Journal of Scientific Research and Management (IJSRM), 2018
Naproxen (N) is a member of nonsteroidal anti-inflammation drug and widely used as an analgesic, antipyretic, and anti-inflammation agent. In this investigation, the inherent stability and biochemical interaction of Naproxen and its related molecules have been studied. Density functional theory (DFT) with B3LYP/ 6-31G (d, p) has been employed to optimize the structures. Frontier molecular orbital features (HOMO-LUMO gap, hardness, softness), dipole moment, electrostatic potential and thermodynamic properties (electronic energy, enthalpy, Gibb’s free energy) of these optimized drugs are investigated. Molecular docking has been performed against prostaglandin H2 (PGH2) synthase protein 5F19 to search the binding affinity and mode(s) of all compounds. It is found that, all compounds are thermodynamically stable; some of them are chemically more reactive and show better binding affinity than the parent drug. ADMET calculations predict the improved pharmacokinetic properties of all compo...
Heliyon, 2021
Cyclooxygenase-2 (COX-2) enzyme inhibitors have not eliminated the necessity for developed drugs not only in the nonsteroidal anti-inflammatory drug (NSAIDs) area, but also in other therapeutic applications including prevention of cancer and Alzheimer's disease. A series of novel substituted cyclic imides have been reported as selective COX-2 inhibitors. To understand the structural features responsible for their activity, a 3D validated pharmacophore and quantitative structureÀactivity relationship (QSAR) model have been developed. The values of enrichment factor (EF), goodness of hit score (GH), area under the ROC curve (AUC), sensitivity, and specificity refer to the good ability of the pharmacophore model to identify active compounds. Multiple linear regression (MLR) produced statistically significant QSAR model with (R 2 training ¼ 0.763, R 2 test ¼ 0.96) and predictability (Q 2 training ¼ 0.66, Q 2 test ¼ 0.84). Then, using the pharmacophore and QSAR models, eight authenticated botanicals in two herbal medicines and the ZINC compounds database, were virtually screened for ligands to COX-2. The retrieved hits which also obey lipinski's rule of five (RO5) were docked in the COX-2 3D structure to investigate their binding mode and affinity. Finally, based on the docking results, nine molecules were prioritized as promising hits that could be used as leads to discover novel COX-2 inhibitors. COX-2 inhibition of most of these hits has not been reported previously. Ten-nanosecond molecular dynamics simulation (10-ns MD) was performed on the initial structure COX-2 complex with ZINC000113253375 and ZINC000043170560 resulted from the docking. Our utilization of the 3D pharmacophore model, QSAR, molecular docking, and molecular dynamics simulation trials can be a potent strategy to successfully predict activity, efficiently design drugs, and screen large numbers of new compounds as active drug candidates.
3D QSAR AND DOCKING STUDY OF INDOLE DERIVATIVES AS SELECTIVE COX-2 INHIBITORS
International Journal of Pharmacy and Pharmaceutical Sciences, 2019
Objective: Non-steroidal anti-inflammatory agents (NSAIDs) continue to be one of the most widely used groups of therapeutic agents. QSAR (quantitative structure-activity relationship) approach is a very useful and widespread technique for drug design. 3D QSAR facilitates evaluation of three-dimensional molecular fields around molecules and generates a relationship of these fields' values with the activity. Methods: 3D QSAR study was performed on selected twenty-four compounds from synthesized indole derivatives using the stepwise variable selection k-nearest neighbor (kNN) molecular field analysis approach for indicating the contribution of the steric and electronic field for activity. The docking study was performed to further confirm the binding affinity of synthesized molecules (ligands) to COX-2 enzyme as well as to study binding nature. Results: Statistically significant model was generated using VLife Molecular Design Suite 3.5 software with cross-validated correlation coefficient q 2 of 0.9461 and high predictive correlation coefficient (Pred_r 2) of 0.8782 indicating that the model is robust. The results of docking study suggest that the synthesized compounds have a comparable binding affinity with the COX-2 enzyme. Conclusion: The present study may prove to be helpful in the development and optimization of existing indole derivatives as anti-inflammatory agents with selective COX-2 inhibition.
Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis
Journal of Computer-Aided Molecular Design, 2004
The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex Ò ) and rofecoxib (Vioxx Ò ). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic.
Internet Elect. J. of Mol. …, 2004
Motivation. Three-dimensional structures of pharmacologically important macromolecules offer a route to the discovery of new drugs. Understanding the macromolecule-ligand interactions and validation of method used for docking and virtual screening of chemical databases is crucial step in structure-based design. We therefore carried out molecular docking for a set of eighty two structurally diverse COX-1/COX-2 inhibitors including traditional NSAIDs and the recent developed coxibs using FlexX method to find out how good this method differentiate between the active and inactive compounds. Method. FlexX is one of the fast flexible docking method that uses an incremental construction algorithm to place ligands into an active site. The scoring function (empirical binding free energy) of the flexX used to estimate the free binding energy of the protein-ligand complex is called F_score. Results. Reproducibility of the experimental conformations of the bound ligands such as SC-558, indomethacin, flurbiprofen indicates the better performance of FlexX method. Good correlation between the standard FlexX score (F_score) and the COX-2 inhibitory activity (pIC 50) was observed. Simple linear regression analysis provided the correlation coefficient values of 0.731 and 0.670 for two classes of COX-2 inhibitors. Conclusions. Flexible docking of eighty two structurally diverse COX-2 inhibitors have been successfully carried out. Some false positives and false negatives were observed but considering the limitations of the available docking programs, the results are encouraging. The detailed analysis of the resulted COX-2-ligand complexes may improve our knowledge in understanding the binding interactions in detail. Thus, this study will be useful for the design of novel COX-2 inhibitors based on docking and the resulted bioactive conformations of the ligands will be useful in building structure-based 3-D QSAR model.