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Background: Currently, endoscopy with biopsy is still considered the gold standard for the evaluation and diagnosis of mucosal inflammation and a number of scores exist to assess endoscopic activity in Crohn’s disease (CD) and ulcerative colitis (UC). Aim and objectives: the aim of the study was to determine the benefit of using both of fecal markers (calprotectin and lactoferrin) in patients presenting with chronic diarrhea and recurrent abdominal pain for differentiation between organic diseases, particularly inflammatory bowel disease (IBD) from non-organic disease, making colonoscope unnecessary. Subjects and methods: This prospective, observational and analytic study was carried out on 44 children who fulfilling the designed inclusion criteria. The study was carried out from Outpatient Clinic of Pediatric gastroenterology unit and from the Inpatient Units of the Pediatric department Faculty of Medicine, Al-Azhar University Hospitals (Al-Hussein & Sayed Galal Hospitals), as well as referral from other hospitals complaining of recurrent abdominal pain and chronic diarrhea from March 2020 to March 2022. Results: there was statistically significant difference between IBD group and functional abdominal pain group as regard fecal calprotectin with p-value≤ 0.001. There was statistically significant difference between IBD group and functional abdominal pain group as regard fecal lactoferrin with p-value≤ 0.001.

In this article, 34 anticoagulant drugs were screened in silico against the main protease (M

In this article, we describe a set of subsequent five-steps chemical reactions to synthesize a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (

Preclinical and clinical studies on mebendazole revealed its potential as an anticancer agent. We therefore aimed to investigate its binding interactions with one of the most important cancer targets (the tubulin protein) depending on its structural similarity with the original co-crystallized ligand (nocodazole), besides characterization of the electronic configuration at the molecular level. By reviewing the binding mode and hydrogen bond lengths between the three polymorphs of mebendazole (MBZ) and the colchicine binding site on the tubulin protein, form B of MBZ is the form expected to bind more efficiently with the tubulin protein among the other forms. The calculated physicochemical properties revealed also that form B is the most lipophilic form, and hence can more flawlessly cross the blood brain barrier in order to target brain tumors. Our study has ramifications to consider form B of MBZ in clinical trials of repurposing MBZ in oncology, because only forms A and C have been considered while form B was abandoned.

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure–activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.

The global prevalence of COVID-19 disease and the overwhelming increase in death toll urge scientists to discover new effective drugs. Although the drug discovery process is a challenging and time-consuming, fortunately, the plant kingdom was found to have many active therapeutics possessing broad-spectrum antiviral activity including those candidates active against severe acute respiratory syndrome coronaviruses (SARS-CoV). Herein, nine traditional Chinese medicinal plant constituents from different origins (Glycyrrhizin 1, Lycorine 2, Puerarin 3, Daidzein 4, Daidzin 5, Salvianolic acid B 6, Dihydrotanshinone I 7, Tanshinone I 8, Tanshinone IIa 9) previously reported to exhibit antiviral activity against SARS-CoV were virtually screened in silico (molecular docking) as potential inhibitors of SARS-CoV-2 target proteins. The tested medicinal plant compounds were in silico screened for their activity against two key SARS-CoV-2 target proteins; 3CLpro, and Spike binding-domain proteins. Among the tested medicinal plant compounds, Salvianolic acid B 6 (Sal-B) showed promising binding affinities against the two specified SARS-CoV-2 target proteins compared to the reference standards used. Hence molecular dynamics simulations followed by calculating the free-binding energy were carried out for Sal-B providing information on its affinity, stability, and thermodynamic behavior within the two SARS-CoV-2 target proteins as well as key ligand-protein binding aspects. Besides, the quantum mechanical calculations showed that Sal-B can adopt different conformations due to the existence of various rotatable bonds. Therefore, the enhanced antiviral activity of Sal-B among other studied compounds can be also attributed to the structural flexibility of Sal-B. Our study gives an explanation of the structure activity relationship required for targeting SARS-CoV-2 3CLpro and Spike proteins and also facilitates the future design and synthesis of new potential drugs exhibiting better affinity and specificity. Besides, an ADME study was carried out on screened compounds and reference controls revealing their pharmacokinetics properties. Communicated by Ramaswamy H. Sarma

The global breakout of COVID-19 and raised death toll has prompted scientists to develop novel drugs capable of inhibiting SARS-CoV-2. Conducting studies on repurposing some FDA-approved glucocorticoids can be a promising prospective for finding a treatment for COVID-19. In addition, the use of anti-inflammatory drugs, such as glucocorticoids, is a pivotal step in the treatment of critical cases of COVID-19, as they can provoke an inflammatory cytokine storm, damaging lungs. In this study, 22 FDA-approved glucocorticoids were identified through in silico (molecular docking) studies as the potential inhibitors of COVID-19's main protease. From tested compounds, ciclesonide 11, dexamethasone 2, betamethasone 1, hydrocortisone 4, fludrocortisone 3, and triamcinolone 8 are suggested as the most potent glucocorticoids active against COVID-19's main protease. Moreover, molecular dynamics simulations followed by the calculations of the binding free energy using MM-GBSA were carried out for the aforementioned promising candidate-screened glucocorticoids. In addition, quantum chemical calculations revealed two electron-rich sites on ciclesonide where binding interactions with the main protease and cleavage of the prodrug to the active metabolite take place. Our results have ramifications for conducting preclinical and clinical studies on promising glucocorticoids to hasten the development of effective therapeutics against COVID-19. Another advantage is that some glucocorticoids can be prioritized over others for the treatment of inflammation accompanying COVID-19.

Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole > Oxfendazole > Nocodazole > Mebendazole > Albendazole > Oxibendazole > Fenbendazole > Ciclobendazole > Thiabendazole > Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate.

Tyrosine kinase inhibitors (TKI) are an important class of molecules. Specific interactions of TKI with water are of interest since they appear in high resolution X-ray structures of TKI–protein complexes and are thought to be important determinants of drug efficacy. Methods for determining the specific interactions of TKI with water molecules in solution are therefore highly desirable. Recently, we revealed that the TKI, AG1478, exhibits absorbance and fluorescence spectra which are sensitive to the conformation of the molecule and the polarity of the surrounding environment. In the present work, we investigated the potential hydrogen bond binding sites of AG1478 using spectroscopic measurements of acetonitrile–water solutions. UV-Vis absorbance spectroscopy of AG1478 revealed H-bond interactions between water molecules and AG1478 in the ground state, as evidenced by changes in spectral shape and optical density with increases in water fraction. The fluorescence spectra of AG1478 in acetonitrile were also greatly influenced by water interactions, revealing fluorescence quenching (by 80%) with the addition of 2% by volume of water. The AG1478 fluorescence quantum yield decreased with increasing temperature in neat acetonitrile but revealed an unorthodox increase with increasing temperature in acetonitrile–water solution. Taken together, these changes are consistent with a specific complex or complexes formed between AG1478 and water molecules. Potential AG1478–water clusters were investigated using ab initio calculations. The effects of explicit hydrogen bonding on vertical excitation, topology and electronic configuration of AG1478 were examined computationally.

The ultimate understanding of drug–protein interactions relies on understanding drug behaviours in solution, at the molecular level. The conformation of a drug contributes to drug–protein docking, hence, drug potency and spectroscopy. Some drugs, such as the anti-cancer drug SKF86002, are chromophores, which are promising tools for optical reporting, as they may change colour or fluorescence when interacting with cells. In the present study, four conformers of the tyrosine kinase inhibitor SKF86002 (stability: B > A > C > D) were obtained with B and A from this study through optimisation, and C and D from the literature. As the global energy minimum structure, SKF86002B is 0.17 kcal mol−1, 10.75 kcal mol−1 and 12.52 kcal mol−1 lower in energy than A, C and D, respectively. Although the total energy difference is small between B and A, the orientation of the fluorophenyl and the pyridinyl rings with respect to the heterocyclic imidazothiazole ring i.e., the shape, is quite different. The UV-Vis spectra of the conformers in dichloromethane solution were calculated using time dependent density functional theory. The absorption spectra of A, B and C exhibit two major bands at 325.3 nm and 240.4 nm, in the vicinity of the measured bands, whereas D displays one major band (249.1 nm). In addition, the calculations assign the major bands to different transitions of the conformers, indicating that the UV-Vis spectrum of SKF86002 is, in fact, conformation dependent. The UV-Vis spectra of SFK86002 may serve as a useful optical reporting property for drug conformational changes in cells.

To understand drug-protein dynamics, it is necessary to account for drug molecular flexibility and binding site plasticity. Herein, we exploit fluorescence from a tyrosine kinase inhibitor, AG1478, as a reporter of its conformation and binding site environment when complexed with its cognate kinase. Water-soluble kinases, aminoglycoside phosphotransferase APH(3')-Ia and mitogen-activated protein kinase 14 (MAPK14), were chosen for this study. On the basis of our prior work, the AG1478 conformation (planar or twisted) was inferred from the fluorescence excitation spectrum and the polarity of the AG1478-binding site was deduced from the fluorescence emission spectrum, while red-edge excitation shift (REES) probed the heterogeneity of the binding site (protein conformation and hydration) distributions in the protein conformational ensemble. In the AG1478-APH(3')-Ia complex, both twisted (or partially twisted) and planar AG1478 conformations were evidenced from emission wavelength-dependent excitation spectra. The binding site environment provided by APH(3')-Ia was moderately polar (λ

AG-1478 (N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinamine) shows promising in vitro and in vivo antiproliferative activity and has gained global interest due to its potent and broad biopharmaceutical activities. An important step towards understanding its spatial and temporal distribution is to determine whether the inhibitors have spectral signatures that might assist in determining the relevant targets and interactions. Its UV-Vis absorption spectra in various solutions have been measured [Khattab et al., Spectrochimica Acta A, 2016, 164, 128]. The present study correlates the UV-Vis spectral signatures with the structure of the drug. Two stable conformers AG-1478B and AG-1478A with close energy values (ΔE = 1.58 kcal mol−1) were located on the potential energy surface through rotation of the single C–N bond of the C–NH–C chain of the drug. The present density functional theory (DFT) study reveals that both conformers contribute to the measured UV-Vis absorption spectrum of AG-1478. The conformers, AG-1478B and AG-1478A, were subjected to further study using molecular orbital theory. It is found that although the conformers are close in energy, the anisotropic properties, such as the shape in three dimensional (3D) space, the dipole moment and the orbitals, are apparently different. The excess orbital energy spectrum (EOES) indicates that six core orbitals exhibit significant conformational changes, exhibiting the signatures of the N atoms, i.e., the NH linker N(25) and the quinazoline N(12). The valence orbitals with significant configurational changes are either due to the local distribution (30a) or delocalization (46a, 76a and 82a (highest occupied molecular orbital (HOMO))).

Tyrosine kinase inhibitors (TKIs) are a major class of drug utilised in the clinic. During transit to their cognate kinases, TKIs will encounter different pH environments that could have a major influence on TKI structure. To address this, we report UV-Vis spectroscopic and computational studies of the TKI, AG1478, as a function of pH. The electronic absorption spectrum of AG1478 shifted by 10 nm (from 342 nm to 332 nm) from acid to neutral pH and split into two peaks (at 334 nm and 345 nm) in highly alkaline conditions. From these transitions, the pKa value was calculated as 5.58 ± 0.01. To compute structures and spectra, time-dependent density functional theory (TD-DFT) calculations were performed along with conductor-like polarizable continuum model (CPCM) to account for implicit solvent effect. On the basis of the theoretical spectra, we could assign the AG1478 experimental spectrum at acidic pH to a mixture of two twisted conformers (71% AG1478 protonated at quinazolyl nitrogen N(1) and 29% AG1478 protonated at quinazolyl nitrogen N(3)) and at neutral pH to the neutral planar conformer. The AG1478 absorption spectrum (pH 13.3) was fitted to a mixture of neutral (70%) and NH-deprotonated species (30%). These studies reveal a pH-induced conformational transition in a TKI.

Recently a dramatic development of the cancer drug discovery has been shown in the field of targeted cancer therapy. Checkpoint kinase 2 (Chk2) inhibitors offer a promising approach to enhance the effectiveness of cancer chemotherapy. Accordingly, in this study many pyrimidine-benzimidazole conjugates were designed and twelve feasible derivatives were selected to be synthesized to investigate their activity against Chk2 and subjected to study their antitumor activity alone and in combination with the genotoxic anticancer drugs cisplatin and doxorubicin on breast carcinoma, (ER+) cell line (MCF-7). The results indicated that the studied compounds inhibited Chk2 activity with high potency (IC50 = 5.56 nM - 46.20 nM). The studied candidates exhibited remarkable antitumor activity against MCF-7 (IG50 = 6.6 μM - 24.9 μM). Compounds 10a-c, 14 and 15 significantly potentiated the activity of the studied genotoxic drugs, whereas, compounds 9b and 20–23 antagonized their activity. Moreover, the combination of compound 10b with cisplatin revealed the best apoptotic effect as well as combination of compound 10b with doxorubicin led to complete arrest of the cell cycle at S phase where more than 40% of cells are in the S phase with no cells at G2/M. Structure-activity relationship was discussed on the basis of molecular modeling study using Molecular modeling Environment program (MOE).

A series of (benzimidazol-2-yl)-aniline ( 1 ) derivatives has been synthesized and evaluated as glycogen phosphorylase (GP) inhibitors. Kinetics studies revealed that compounds displaying a lateral heterocyclic residue with several heteroatoms (series 3 and 5) exhibited modest inhibitory properties with IC 50 values in the 400–600 μM range. Arylsulfonyl derivatives 7 (Ar: phenyl) and 9 (Ar: o -nitrophenyl) of 1 exhibited the highest activity (series 2) among the studied compounds (IC 50 324 μM and 357 μM, respectively) with stronger effect than the p -tolyl analogue 8 .

We studied the spectroscopic characteristics of SKF86002, an anti-inflammatory and tyrosine kinase inhibitor drug candidate. Two conformers SKF86002A and SKF86002B are separated by energy barriers of 19.68 kJ·mol − 1 and 6.65 kJ·mol − 1 due to H-bonds, and produce the three major UV–Vis absorption bands at 325 nm, 260 nm and 210 nm in cyclohexane solutions. This environment-sensitive fluorophore exhibited emission in the 400–500 nm range with a marked response to changes in environment polarity. By using twenty-two solvents for the solvatochromism study, it was noticed that solvent polarity, represented by dielectric constant, was well correlated with the emission wavelength maxima of SKF86002. Thus, the SKF86002 fluorescence peak red shifted in aprotic solvents from 397.5 nm in cyclohexane to 436 nm in DMSO. While the emission maximum in hydrogen donating solvents ranged from 420 nm in t -butanol to 446 nm in N -methylformamide. Employing Lippert-Mataga, Bakhshiev and Kawski models, we found that one linear correlation provided a satisfactory description of polarity effect of 18 solvents on the spectral changes of SKF86002 with R 2 values 0.78, 0.80 and 0.80, respectively. Additionally, the multicomponent linear regression analysis of Kamlet-Taft ( R 2 = 0.94) revealed that solvent acidity, basicity and polarity accounted for 31%, 24% and 45% of solvent effects on SKF86002 emission, respectively. While Catalan correlation ( R 2 = 0.92) revealed that solvatochromic change of SKF86002 emission was attributed to changes in solvent dipolarity (71%), solvent polarity (12%), solvent acidity (11%) and solvent basicity (6%). Plot of Reichardt transition energies and emission energies of SKF86002 in 18 solvents showed also a linear correlation with R 2 = 0.90. The dipole moment difference between excited and ground state was calculated to be 3.4–3.5 debye.

Background The study was aimed at investigating the effect of various solvents on the absorption spectra of Neutral Red, a dye belonging to the quinone-imine class of dyes. The solvents chosen for the study were water, ethanol, acetonitrile, acetone, propan-1-ol, chloroform, nitrobenzene, ethyleneglycol, acetic acid, DMSO and DMF. Results The results have shown that the absorption maxima of dyes are dependent on solvent polarity. In non-hydrogen-bond donating solvents, solvation of dye molecules probably occurs via dipole-dipole interactions, whereas in hydrogen-bond donating solvents the phenomenon is more hydrogen bonding in nature. To estimate the contribution of the different variables on the wave number of the Neutral Red dye, regression analyses using the ECW model were compared with the π* scale model. This showed that the unified scale for estimating the solvent effect on the absorption of the Neutral Red dye is more adopted and more applicable than the π* scale model. Conclusion Absorption maxima of dyes are dependent on solvent polarity. Solvation of dye molecules probably occurs via dipole-dipole interactions in non-hydrogen-bond donating solvents, whereas in hydrogen-bond donating solvents the phenomenon is more hydrogen bonding in nature. The unified scale for estimating the solvent effect on the absorption of Neutral Red dye is more adopted and more applicable than the π* scale model. This may be due to complications from both π-π* charge transfer interactions and incomplete complexation of the solute; these effects are averaged out in the derived β and π parameters and thus limit their applicability.