In Silico Pharmacology最新文献

In this study, the release characteristics of gliclazide in a polymeric matrix system, which is used for controlled drug release purposes, are conducted experimentally and numerically. A code using the finite element method predicting the drug release behavior of gliclazide matrix system in an aqueous medium is developed. The parameters having significant importance in drug release kinetics, such as structure factor, the slab's size and shape are varied systematically. The consistent reduction in the solid drug during the dissolution process is evaluated. The numerical data agree well with the experimental results. Therefore, the controlled drug release of gliclazide is accurately modeled by the present numerical code. The results imply that the porosity of the matrix system has the most significant effect on the drug dissolution rate. The reduction in the tablet's diameter and utilization of cylindrical slab geometry increases the speed of the drug dissolution in the aqueous medium.

Diabetes mellitus is a metabolic syndrome characterized by elevated blood glucose. The α-glucosidase enzyme is responsible for the hydrolysis of carbohydrates. This in silico study aimed to evaluate the inhibitory effects of the isolated compounds from Allium sativum L. on α-glucosidase. At first, sulfur and phenolic compounds of A. sativum L. were obtained from PubChem database, and α-glucosidase enzyme structure was obtained from Protein Data Bank. Toxicity class of compounds and the Lipinski parameter were predicted by Toxtree and Protox II and the Swiss ADME tools, respectively. Finally, the molecular interaction analysis between α-glucosidase and compounds from A. sativum L. was performed by AutoDock 4.2.6. Molecular interactions were investigated using Discovery Studio Visulizer and Ligplot 2.1 program. All of the selected sulfur and phenolic compounds from A. sativum L. followed the Lipinski's rules, had an acceptable binding energy, and lacked toxicity; therefore, they were appropriate candidates for α-glucosidase inhibition. Among these compounds, methionol and caffeic acid showed the lowest binding energy, and the highest inhibitory effect on α-glucosidase enzyme with - 3.9 and - 4.8 kcal/mol, respectively. These compounds also indicated the lower binding energy than the standard inhibitor (miglitol). Among the sulfur and phenolic compounds in A. sativum L., methionol and caffeic acid were predicted to be the powerful inhibitors, due to having more hydrogen binds and hydrophobic interactions with the active site of α-glucosidase.

The widespread of coronavirus (COVID-19) is a new global health crisis that poses a threat to the world. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in bats and was discovered first in Wuhan, Hubei province, China in December 2019. Immunoinformatics and bioinformatics tools were employed for the construction of a multi-epitope subunit vaccine to prevent the diseases. The antigenicity, toxicity and allergenicity of all epitopes used in the construction of the vaccine were predicted and then conjugated with adjuvants and linkers. Vaccine Toll-Like Receptors (2, 3, 4, 8 and 9) complex was also evaluated. The vaccine construct was antigenic, non-toxic and non-allergic, which indicates the vaccines ability to induce antibodies in the host, making it an effective vaccine candidate.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-020-00062-x.

SARS-CoV-2 is a new strain of coronavirus that appeared in China in December 2019, in recent years, great progress has been made in developing new antiviral drugs, and natural products, are important sources of potential and new antiviral drugs. The present study aimed to assess some biologically active compounds present in medicinal plants as potential COVID-19 inhibitors, using molecular docking methods. The Docking study was performed by Molecular Operating Environment software (MOE). About 20 Compounds were screened in this study; these compounds were selected based on classification of their chemical origin and their antiviral activity from literature. These compounds might be used to inhibit COVID-19 infection. The results demonstrate the effectiveness of this screening strategy, which can lead to rapid drug discovery in response to new infectious diseases. The results showed that many compounds isolated from medicinal plants such as; Gallic acid (- 17.45), Quercetin (- 15.81), Naringin (- 14.50), Capsaicin (- 13.90), and Psychotrine (- 13.5) are important sources for novel antiviral drugs targeting COVID-19.

It is no longer news that a novel strain of coronavirus named SARS-CoV-2 is ravaging the health sector worldwide, several attempts have been made to curtail this pandemic via repurposing of old drugs but at the present, available drugs are not adequately effective. Over the years, plant phytochemicals are increasingly becoming alternative sources of antimicrobial agents with novel mechanisms of action and limited side effects compared to synthetic drugs. Isolated saponins and tannins were evaluated for antiviral activity against SARS-CoV-2 (M^pro) via Molecular Docking and it was observed that a handsome number of the phytochemicals had binding affinities much better than Remdesivir, Dexamethasone, and N3 inhibitor which were used as the standards in this study. Further investigation of drug-likeness, ADMET profile, PASS profile, oral bioavailability, bioactivity, binding mode, and molecular interactions of these phytochemicals revealed that binding affinity alone is not enough to justify the potency of a molecule in the drug discovery process, as only 4 among the screened compounds passed all the analyses and are identified as potential inhibitors of SARS-CoV-2 (M^pro). This preliminary study thereby recommends Ellagic acid (- 8.4 kcal/mol), Arjunic Acid (- 8.1 kcal/mol), Theasapogenol B (- 8.1 kcal/mol), and Euscaphic Acid (- 8.0 kcal/mol) as potential inhibitors of SARS-CoV-2 (M^pro) with better pharmacokinetics and bioavailability compared to Remdesivir which is currently used compassionately.

Bordetella pertussis and Bordetella parapertussis are Gram-negative, aerobic, and pathogenic bacteria and cause pertussis disease (whooping cough) in humans. Genomic island analysis indicated the presence of an important protein bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (BMD/MC) in both B. pertussis and B. parapertussis. BMD/MC is associated with carbon fixation, folate pathway, and microbial metabolism in a diverse environment. Sequence comparison analysis indicates two amino acid variations between BMD/MC of B. pertussis and B. parapertussis and this difference reflects a good extent of variation in their 3D model. After refinement, BMD/MC model assessment result shows that 96.77% residue of B. pertussis and 97.49% residues of B. pertussis belong to the favored region of the Ramachandran plot, indicating a good quality model. During structural alignment, chain A of BMD/MC for B. pertussis and B. parapertussis shows the RMSD of 0.058 angstroms between 281 pruned atom pairs. Cavity analysis predicts a single cavity with an area (362.723 Ų) and volume (216.631 ų) in the BMD/MC of B. pertussis, whereas the area and volume of cavity in B. parapertussis is 479.689 Ų and 350.982 ų respectively. Several residues in the predicted cavity of both organisms are common with a good extent of variation in their area and volume. The average value of RMSD, RMSF, the radius of gyration, and principal component analysis (eigenvectors) for the BMD/MC model (B. parapertussis) was found smaller as compared to B. pertussis, which indicates that the B. parapertussis model is comparatively better than B. pertussis. MDS analysis suggests that both modeled structures are stable, good quality, and a compact model with a small degree of motions.

P-glycoprotein (P-gp), which was first identified in cancer cells, is an ATP-dependent efflux transporter that expels a wide variety of cytotoxic compounds out of cells. This transporter can decrease the bioavailability of therapeutic drugs by preventing their sufficient intracellular accumulation. Over expression of P-gp in cancer cells lead to multidrug resistance (MDR) phenotype that is one of the main reasons for the failure of chemotherapy. Hence, P-gp inhibition is a favorable method to reverse MDR. In this study, the lignanamides from Cannabis sativa were docked against P-gp to recognize potential binding affinities of these phytochemicals. Tariquidar and zosuquidar, two well-known P-gp inhibitors, were selected as the control ligands. It was observed that cannabisin M and cannabisin N exhibited higher binding affinities (- 10.2 kcal/mol) to drug-binding pocket of P-gp when compared with tariquidar and zosuquidar that showed binding affinities of - 10.1 and - 9.6 kcal/mol, respectively. Based on these findings, cannabisin M and cannabisin N could be good drug candidates against P-gp.

Diabetes mellitus is a multifactorial disorder characterized by a chronic elevation in blood glucose levels. Currently, antidiabetic drugs are available to counteract the associated pathologies. Their concomitant effects necessitate the investigation for an effective and safe drug aimed to diminish blood glucose levels with fewer side effects. Several researchers are taking new initiatives to explore plant sources as they are known to contain a wide variety of active agents. Hence, the present study was undertaken to study the role of natural products using in silico interaction studies. Erythrin a compound present in lichens was selected as a potential anti-diabetic agent. Molecular docking studies were carried out with 14 target proteins to evaluate its antidiabetic potential. Molecular docking analysis resulted in favourable binding energy of interaction ranging as low as - 119.676 to - 92.9545 kcal/mol for erythrin, Analogue showed the highest interactions with 3C45 (- 119.676 kcal/mol) followed by 2Q5S (- 118.398 kcal/mol), 1XU7 (- 117.341 kcal/mol), 3K35 (- 114.267 kcal/mol). Erythrin was found to fare better than the three clinically used antidiabetic compounds, metformin, repaglinide and sitagliptin. Further, the molecular interactions between erythrin and the diabetes related target proteins was established by analysing the interactions with associated amino acids. In silico pharmacokinetics and toxicity profile of erythrin using admetSAR software predicted erythrin as non-carcinogenic and non-mutagenic. The drug-likeliness was calculated using molsoft software respecting Lipinski's rule of five. The compound was found to comply with Lipinksi rules violating only one filter criterion. The study suggested that erythrin could be a potential anti-diabetic agent.

Glaucoma, the most perilous disease leading to blindness is a result of optical neuropathy. Accumulation of aqueous humor in the posterior chamber due to a large difference in the rate of formation and its drainage in the anterior chamber causes an increase in intraocular pressure (IOP) leading to damage of nerve cells. A literature survey has revealed that inhibition of the Rho guanosine triphosphatases (rho GTPase) pathway by specific inhibitors leads to the relaxation of contractile cells involved in the aqueous outflow pathway. Relaxation of the strained contractile cells results in increased outflow thereby releasing IOP. In the present study molecular docking has been used to screen twenty seven bioactive (17 natural compounds and 10 conventional drugs) compounds that may play a significant role in relaxing contractile cells by inhibiting rho-GTPase protein. Docking results showed that among all-natural bioactive compounds Cyanidin and Delphinidine have a good binding affinity (- 8.4 kcal/mol) than the top screened conventional drug molecule Mitomycin, (- 6.3 kcal/mol) when docked with rho-GTPase protein. Cyanidin and Delphinidin belong to anthocyanidin, a glycoside form of anthocyanins from Vaccinium myrtillus L. and Punica granatum. The resembling potential of Cyanidin and Delphinidin concerning the drug Mitomycin was confirmed through simulation analysis. Molecular dynamics study (MDS) for 100 ns, showed that the rho GTPase-Delphinidine complex structure was energetically more stable than rho GTPase-Cyaniding complex in comparison to rho GTPase-Mitomycin complex. The comparative study of both the selected hits (Cyanidin and Delphinidin) was assessed by RMSD, RMSF, Rg, SASA, H-bond, PCA MM/PBSA analysis. The analysis revealed that Delphinidine is more potent to inhibit the rho GTPase as compare to Cyaniding and available conventional drugs in terms of stability and binding free energy. Based on the results, these molecules have good pharmacokinetic and pharmacodynamics properties and will prove to be a promising lead compound as a future drug for Glaucoma.

Traditionally, Tinospora cordifolia is commonly used in the treatment of diabetes and obesity; has been evaluated for their anti-diabetic and anti-obese potency in experimental animal models. However, the binding affinity of multiple bioactives with various proteins involved in the pathogenesis of diabetes and obesity has not been reported yet. Hence, the present study aimed to assess the binding affinity of multiple bioactives from T. cordifolia with various targets involved in the pathogenesis of diabetes and obesity. The ligands and targets were retrieved from the PubChem and Protein Data Bank respectively and docked using autodock4.0. Druglikeness and absorption, distribution, metabolism, excretion, and toxicity profile were predicted using Molsoft and admetSAR1 respectively. The multiple bioactives from T. cordifolia were identified to interact with multiple proteins involved in the pathogenesis of diabetes/obesity, i.e., isocolumbin (- 9 kcal/mol) with adiponectin (PDB: 4DOU), β-sitosterol (- 10.9 kcal/mol) with cholesteryl ester transfer protein (PDB: 2OBD), tinocordiside (- 6.9 kcal/mol) with lamin A/C (PDB: 3GEF), berberine (- 9.5 kcal/mol) with JNK1 (PDB:3ELJ), β-sitosterol & isocolumbin (- 10.1 kcal/mol) with peroxisome proliferator-activated receptor-γ (PDB:4CI5), berberine (- 7.5 kcal/mol) with suppressor of cytokine signaling 3 (PDB: 2BBU), isocolumbin (- 9.6 kcal/mol) with pancreatic α-amylase (PDB: 1B2Y), isocolumbin (- 9 kcal/mol) with α-glucosidase (PDB: 3TOP), and β-sitosterol (- 10.8 kcal/mol) with aldose reductase (PDB: 3RX2). Similarly, among the selected bioactives, tembetarine scored highest druglikeness score, i.e., 1.21. In contrast, isocolumbin scored lowest drug-likeness character i.e. - 0.52. The predicted result of phytochemicals from T. cordifolia for acute oral toxicity, rat acute toxicity, fish toxicity, drug-likeness score, and aqueous solubility showed the probability of lower side/adverse effects in human consumption. The study suggests processing for bioactives from T. cordifolia against diabetes and obesity via in-vitro and in-vivo approaches.