QSAR analysis of coumarin-based benzamides as histone deacetylase inhibitors using CoMFA, CoMSIA and HQSAR methods

Histone deacetylases (HDACs) as the promising therapeutic targets for the treatment of cancer and other diseases, modify chromatin structure and contribute to aberrant gene expression in cancer. Inhibition of HDACs is emerging as an important strategy in human cancer therapy and HDAC inhibitors (HDACIs) enable histone to maintain a high degree of acetylation. In this work, molecular modeling studies, including CoMFA, CoMFA-RF, CoMSIA and HQSAR and molecular docking were performed on a series of coumarin-based benzamides as HDAC inhibitors. The statistical qualities of generated models were justified by internal and external validation, i.e., cross-validated correlation coefficient (q2), non-crossvalidated correlation coefficient (r2 ncv) and predicted correlation coefficient (r2 pred), respectively. The CoMFA (q2, 0.728; r2 ncv, 0.982; r2 pred; 0.685), CoMFA-RF (q2, 0.764; r2 ncv, 0.960; r2 pred; 0.552), CoMSIA (q2, 0.671; r2 ncv, 0.977; r2 pred; 0.721) and HQSAR models (q2, 0.811; r2 ncv, 0.986; r2 pred; 0.613) for training and test set of HDAC inhibition of HCT116 cell line yielded significant statistical results. Therefore, these QSAR models were excellent, robust and had better predictive capability. Contour maps of the QSAR models were generated and validated by molecular docking study. The final QSAR models could be useful for the design and development of novel potent HDAC inhibitors in cancer treatment. The amido and amine groups of benzamide part as scaffold and the bulk groups as a hydrophobic part were key factors to improve inhibitory activity of HDACIs

Preparation and In vitro Evaluation of Intelligent Blood Glucose Regulating Nanonetwork Based on PLGA and Chitosan Nanoparticles

Introduction: Intelligent systems which release insulin in response to glucose level have been investigated thoroughly and many researches work in this area. In this work we present preparation and characterization of a novel Nano system composed of chitosan and PLGA nanoparticles, incorporating insulin, glucose oxidase and catalase. Methods and Results: Chitosan nanoparticles were prepared through ionic gelation method. First chitosan solution (2 mg/ml) in acetic acid 1% (v/v) was prepared. 2 mg insulin was dissolved in 5 ml of this solution. TPP solution was added dropwise. Stirring the solution was continued for 1 hour. Chitosan nanoparticles were separated by ultracentrifugation. Size of these nanoparticles was found to be 180-200 nm. Preparation of PLGA nanoparticles containing glucose oxidase (GOx) and catalase (CAT) was done by double emulsification technique.  PLGA was dissolved in ethyl acetate then aqueous solution of GOx and CAT were added to this organic phase. Sonication was performed to prepare w1/o emulsion. Deionized water was added and by second sonication w1/o/w2 emulsion was formed. Theorganic phase was removed by vacuum rotary evaporator and nanoparticles were separated through filtration, in size range of 130-150 nm. Chitosan NPs were added to PLGA NPs and the Nano system was formed through an electrostatic attraction between two oppositely charged particles. In vitro insulin release from this Nano system was investigated through radiolabeling method at two different glucose concentrations of 70 and 400 mg/dl. Conclusions: At high glucose concentration after glucose entrance into PLGA NPs it was converted to gluconic acid. Lowering of the Nano system microenvironment pH caused protonation and swelling of chitosan NPs and hence insulin release

Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents

Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. It has four classes (I-IV), among them especially class I isozyme are involved in promoting tumor cells proliferation, angiogenesis, differentiation, invasion and metastasis and also viable targets for cancer therapeutics. A novel series of coumarin-based benzamides was designed and synthesized as HDAC inhibitors. The cytotoxic activity of the synthesized compounds (8a-u) was evaluated against six human cancer cell lines including HCT116, A2780, MCF7, PC3, HL60 and A549 and a single normal cell line (Huvec). We evaluated their inhibitory activities against pan HDAC and HDAC1 isoform. Four compounds (8f, 8q, 8r and 8u) showed significant cytotoxicity with IC50 in the range of 0.53–57.59 μM on cancer cells and potent pan-HDAC inhibitory activity (consists of HDAC isoenzymes) (IC50 = 0.80–14.81 μM) and HDAC1 inhibitory activity (IC50 = 0.47–0.87 μM and also, had no effect on Huvec (human normal cell line) viability (IC50 > 100 μM). Among them, 8u displayed a higher potency for HDAC1 inhibition with IC50 value of 0.47 ± 0.02 μM near equal to the reference drug Entinostat (IC50 = 0.41 ± 0.06 μM). Molecular docking studies and Molecular dynamics simulation of compound 8a displayed possible mode of interaction between this compound and HDAC1enzym

Synthesis and Effects of 4,5-Diaryl-2-(2-alkylthio-5-imidazolyl) Imidazoles as Selective Cyclooxygenase Inhibitors

Objective(s)In recent years highly selective COX-2inhibitors were withdrawn from the market because of an increased risk of cardiovascular complications. In this study we were looking for potent compounds with moderate selectivity for cox-2. So, four analogues of 4, 5-diaryl-2-(2-alkylthio-5-imidazolyl) imidazole derivatives were synthesized and their anti-inflammatory and anti-nociceptive activities were evaluated on male BALB/c mice (25-30 g). Molecular modeling and in vitro COX-1 and COX-2 isozyme inhibition studies were also performed. Materials and Methods2-(2-Alkylthio-5-imidazolyl)-4,5-diphenylimidazole compounds were obtained by the reaction of benzyl with 2-alkylthio-1-benzylimidazole-5-carbaldehyde, in the presence of ammonium acetate. Spectroscopic data and elemental analysis of compounds were obtained and their structures elucidated. Anti-nociception effects were examined using writhing test in mice. The effect of the analogues (7.5, 30, 52.5 and 75 mg/kg) against acute inflammation were studied using xylene-induced ear edema test in mice. Celecoxib (75 mg/kg) was used as positive control.ResultsAll four analogues exhibited anti-nociceptive activity against acetic acid induced writhing, but did not show significant analgesic effect (P< 0.05) compared with celecoxib. It was shown that analogues injected 30 min before xylene application reduced the weight of edematic ears. All analogues were found to have less selectivity for COX-2 in comparison to celecoxib. ConclusionInjected doses of synthesised analogues possesses favorite anti-nociceptive effect and also has anti-inflammatory effects, but comparing with celecoxib this effect is not significantly different. On the other hand selectivity index for analogues is less than celecoxib and so we expect less cardiovascular side effects for these compounds

Effects of 4-(2-Alkylthio-1-benzyl-5-imidazolyl)-Dihydropyridines on the Isolated Rat Colon and Right Atrium Contractility

Abstract Objectives In order to provide a pharmacological profile for some newly synthesized dihydropyridines, we investigated their effects on the isolated rat colon segments and the isolated rat atrium contractility. The tested compounds include alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-alkylthio-1-benzyl-5-imidazolyl substituent, and nifedipine as a positive control substance. Materials and Methods Isolated rat colon and atrial tissues were prepared. Rat colon was contracted with 80 mM KCl, and maximum response was recorded (100%). After washing tissue with Krebs solution it was preincubated with different concentrations of test compounds and again KCl was added and percent change in contraction was calculated. Spontaneous contractions and its frequency for colon and atrium before and after addition of test compounds were also recorded and percent change was calculated. Nifedipine (10 -8 -10 -5 M) was used as positive control at all experiments. Results The compounds showed similar effects to that of nifedipine on the isolated rat colon. The potency of these analogues with concentration range 10 -5 to 10 -4 M was compared to potency of nifedipine which was effective at 10 -8 to 10 -5 M (P&lt;0.01). However, unlike nifedipine, the test compounds exerted significant positive inotropic effect on the isolated rat atrium (P &lt; 0.01). Our observations suggest that these analogues of nifedipine selectively enhance contractility of heart muscle while causing relaxation of intestinal smooth muscle. Conclusion These compounds may serve as valuable probes to develop novel dihydropyridines with dual smooth muscle relaxant effect and positive inotropic action

Evaluation of apigenin-based biflavonoid derivatives as potential therapeutic agents against viral protease (3CLpro) of SARS-CoV-2 via molecular docking, molecular dynamics and quantum mechanics studies

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic COVID-19 disease that affects human respiratory function. Despite the scientific progression made in the development of the vaccine, there is an urgent need for the discovery of antiviral drugs for better performance at different stages of SARS-CoV-2 reproduction. The main protease (Mpro or 3CLpro) plays a pivotal role in the life cycle of the virus, making it an attractive target for the development of antiviral agents effective against the new strains of coronaviruses (CoVs). In this study, a series of apigenin-based natural biflavonoid derivatives as potential inhibitors of coronaviruses 3CLpro was investigated by in silico approaches. For this purpose, the molecular docking was performed to analyze the interaction of the natural biflavonoids with SARS-Cov-2 main protease and for further investigation, docking to the 3CLpro of SARS-CoV and MERS-CoV. Based on docking scores and comparison with the reference inhibitors (ritonavir and lopinavir), more than half of the biflavonoids had strong interactions with the residues of the binding pocket of the coronaviruses 3CLpro and exhibited better binding affinities toward the main protease than ritonavir and lopinavir. The top biflavonoids were further explored through molecular dynamics simulation, binding free energy calculation and residual energy contributions estimated by the MM-PBSA. Also, drug likeness property investigation by Swiss ADME tools and density functional theory (DFT) calculations were performed. The results confirmed that the 3CLpro-amentoflavone, 3CLpro-bilobetin, 3CLpro-ginkgetin, and 3CLpro-sotetsuflavone complexes possess a large amount of dynamic properties such as high stability, significant binding energy and fewer conformation fluctuations. Also, the pharmacokinetics and drug-likeness studies and HOMO-LUMO and DFT descriptor values indicated a promising result of the selected natural biflavonoids. Overall findings indicate that the apigenin-based biflavonoids may inhibit COVID-19 by significant interactions in the binding pocket and those results can pave the way in drug discovery although the effectiveness of these bioactive compounds should be further validated by in-vitro and in-vivo investigations

In silico studies of novel scaffold of thiazolidin-4-one derivatives as anti-Toxoplasma gondii agents by 2D/3D-QSAR, molecular docking, and molecular dynamics simulations

Toxoplasma gondii is an obligate intracellular protozoa that can infect a wide variety of warm-blooded animals and humans. It was claimed that novel anti-Toxoplasma gondii agents were optimized as potential drug candidates, designed and created as significant agents. In this work, molecular modeling studies, including CoMFA, CoMFA-RF, CoMSIA, and HQSAR were performed on a set of 59 thiazolidin-4-one derivatives as anti-T. gondii agents. The statistical qualities of generating models were justified by internal and external validation, i.e., cross-validated correlation coefficient (q2), non-cross-validated correlation coefficient (rncv2) and predicted correlation coefficient (rpred2), respectively. The CoMFA (q2, 0.897;rncv2, 0.933; rpred2, 0.938), CoMFA-RF (q2, 0.900;rncv2, 0.935; rpred2, 0.998), CoMSIA (q2, 0.910;rncv2, 0.950; rpred2, 0.998), and HQSAR models (q2, 0.924;rncv2, 0.953; rpred2, 0.995) for training and test set yielded significant statistical results. Therefore, these QSAR models were excellent, robust, and had better predictive capability. Contour maps of the QSAR models were generated and validated by molecular dynamics simulation-assisted molecular docking study. The final QSAR models could be useful for the design and development of novel potent anti-T. gondii agents

Molecular Modeling Studies of Anti-Alzheimer Agents by QSAR, Molecular Docking and Molecular Dynamic Simulations Techniques

Background: Acetylcholinesterase (AChE), a serine hydrolase, is an important drug target in the treatment of Alzheimer's disease (AD). Thus, novel AChE inhibitors were designed and developed as potential drug candidates, for significant therapy of AD. Objective: In this work, molecular modeling studies, including CoMFA, CoMFA-RF, CoMSIA, HQSAR and molecular docking and molecular dynamic simulations were performed on a series of AChE inhibitors to get more potent anti-Alzheimer drugs. Methods: The 2D/3D-QSAR models including CoMFA, CoMFA-Rf, CoMSIA, and H-QSAR methods were carried out on 59 pyrimidinylthiourea derivatives as data set by the Sybylx1.2 program. Molecular docking and molecular dynamic simulation were performed using the MOE software and the Sybyl program, respectively. Partial least squares (PLS) model as descriptors was used for QSAR model generation. Results: The CoMFA (q2, 0.775;〖 r〗_ncv^2, 0.901; 〖 r〗_pred^2, 0.773), CoMFA-RF (q2, 0.629;〖 r〗_ncv^2, 0.901; 〖 r〗_pred^2, 0.824), CoMSIA (q2, 0.754;〖 r〗_ncv^2, 0.919; 〖 r〗_pred^2, 0.874) and HQSAR models (q2, 0.622;〖 r〗_ncv^2, 0.949; 〖 r〗_pred^2, 0.854) for training and test set yielded significant statistical results. Conclusion: These QSAR models were excellent, robust and had good predictive capability. Contour maps obtained from the QSAR models were validated by molecular dynamic simulation-assisted molecular docking study. The resulted QSAR models could be useful for rational design of novel potent AChE inhibitors in Alzheimer's treatment. Keywords: Alzheimer`s disease; CoMFA; CoMSIA; HQSAR; molecular docking; pyrimidinylthiourea derivatives

In Silico Study of Five SARS CoV-2 Target Proteins on Known Drugs: In silico study of five SARS CoV-2 target proteins

COVID-19 is an infectious disease that started at the end of 2019 in China then became pandemic worldwide. A number of crystal structures of coronavirus proteins are available in the Protein Data Bank. In this paper, we reported results from the virtual screening of databases including 2701 FDA approved drugs against five known coronavirus protein targets. Our results showed a wide range of scores for different drugs of which some were predicted to be active against one or some of the proteins. Among all of the compounds with higher scores, tannic acid and cobicistat showed to be active against four and two of the studied proteins respectively. Tannic acid which was reported to be an antiviral and potent inhibitor of hepatitis C virus activity and cobicistat with anti- HIV activity might be useful for the cure of COVID-19. According to the results, we suggest more studies on these valuable potential drugs