Design of 5H-pyrrolo[2,3-b]pyrazine-2-phenyl Ether Derivatives as Potential JAK3 Inhibitor Based on Surflex Docking,3D-QSAR Modeling and Reverse Docking

Tyrosine protein kinase JAK3 has a very important significance on organ transplantation and the treatment of autoimmune diseases, which has been a potential therapeutic target. In recent years, a large number of JAK3 inhibitors have been reported. However, the poor selectivity and side effects have limited their widespread use in clinical practice. In order to solve this problem, 52 potential small-molecule inhibitors were combined with JAK1, JAK2 and JAK3 respectively to obtain the optimal conformation of small molecules. On the basis of that we established 3D quantitative structure-activity relationships（3D-QSAR） model. Comparative molecular field analysis（Co MFA） and molecular similarity analysis（Co MSIA） were used to evaluate the model. We took advantage of reverse docking to explore the underlying toxicity and side effects. Combining 3D quantitative structure-activity relationships, surflex-dock and reverse docking results, ten 5 H-pyrrolo[2,3-b]pyrazine-2-phenyl ether derivatives based on the most optimal selectivity and activity compound 39 were designed. It can be seen from Co MFA and Co MSIA predicted active values of designed molecules that the selectivity of designed small molecules was improved obviously. Among them, compounds 61 and 62 could become the potential small molecule compounds.

Exploration of the mechanisms of Aflatoxin B1 toxicity and the targets of Oltipraz by reverse docking

Aflatoxin B1 toxicity is well known but the mechanism of this toxicity is still unclear. In addition, the target of the anti-aflatoxin chemopreventive drug Oltipraz remains to be identified. In this study, we employed computer aided reverse docking analysis to identify putative targets of Aflatoxin B1（AFB） and Oltipraz. The results showed that the clinically known toxic effects of AFB are related to this molecule＇s strong binding affinity for key proteins involved in cell apoptosis, hormone metabolism, immune suppression, and digestive organ function. In addition, virtual binding assay indicated that Oltipraz neutralizes the toxicity of AFB by inhibiting its biotransformation enzymes. In conclusion, the technique of reverse docking may be used to identify the specific targets of AFB and Oltipraz, and our findings could significantly accelerate the mechanistic studies of the two molecules and provide guidance for the development of anti-AFB drugs.

Evaluating reverse docking on general and selective inhibitors: a case study about glide

As a powerful tool for target prediction,reverse docking remains largely unexplored.The objective evaluation of reverse docking software can help us know better about the strength and weakness of these tools,hence guiding us in target prediction.In the present study,we evaluated the target prediction power of Glide(SP)against general inhibitors and selective inhibitors.The results showed that the scoring tendency could be different for each ligand,and overall scoring sampling was necessary for a better understanding of the docking score for a certain protein-ligand pair.Besides,the input conformation of the binding pocket could affect the docking result.Glide(SP)showed a preferable performance on the target prediction of the general inhibitors.However,the accuracy of the target prediction of the selective inhibitors was relatively low,indicating that Glide(SP)might not be capable for this task.The case study about COVID-19 proved that coagulation factor Xa might be a potential target of chloroquine.Therefore,we recommend the further development of reverse docking tools and rectification of inter-target scoring bias.

Anti-inflammatory effect and antihepatoma mechanism of carrimycin

BACKGROUND New drugs are urgently needed for the treatment of liver cancer, a feat that could be feasibly accomplished by finding new therapeutic purposes for marketed drugs to save time and costs. As a new class of national anti-infective drugs, carrimycin(CAM) has strong activity against gram-positive bacteria and no cross resistance with similar drugs. Studies have shown that the components of CAM have anticancer effects.AIM To obtain a deeper understanding of CAM, its distribution, metabolism and antiinflammatory effects were assessed in the organs of mice, and its mechanism of action against liver cancer was predicted by a network pharmacology method.METHODS In this paper, the content of isovaleryl spiramycin Ⅲ was used as an index to assess the distribution and metabolism of CAM and its effect on inflammatory factors in various mouse tissues and organs. Reverse molecular docking technology was utilized to determine the target of CAM, identify each target protein based on disease type, and establish a target protein-disease type network to ascertain the effect of CAM in liver cancer. Then, the key action targets of CAM in liver cancer were screened by a network pharmacology method, and the core targets were verified by molecular docking and visual analyses.RESULTS The maximum CAM concentration was reached in the liver, kidney, lung and spleen 2.5 h after intragastric administration. In the intestine, the maximum drug concentration was reached 0.5 h after administration. In addition, CAM significantly reduced the interleukin-4(IL-4) levels in the lung and kidney and especially the liver and spleen;moreover, CAM significantly reduced the IL-1β levels in the spleen, liver, and kidney and particularly the small intestine and lung. CAM is predicted to regulate related pathways by acting on many targets,such as albumin, estrogen receptor 1, epidermal growth factor receptor and caspase 3, to treat cancer, inflammation and other diseases.CONCLUSION We determined that CAM inhibited inflammation. We also predicted the complex multitargeted effects of CAM that involve multiple pathways and the diversity of these effects in the treatment of liver cancer, which provides a basis and direction for further clinical research.

Exploring the Pathways and Targets of Shexiang Baoxin Pill for Coronary Heart Disease through a Network Pharmacology Approach

Objective: To investigate the network pharmacology of Shexiang Baoxin pill(SBP) and systematically analyze the mechanisms of SBP.Methods: In this study, we excavated all the targets of 26 constituents of SBP which were identified in rat plasma though literature mining and target calculation(reverse docking and similarity search) and analyzed the multiple pharmacology actions of SBP comprehensively through a network pharmacology approach.Results: In the end, a total of 330 Homo sapiens targets were identified for 26 blood constituents of SBP.Moreover, the pathway enrichment analysis found that these targets mapped into 171 KEGG pathways and 31 of which were more enriched.Among these identified pathways, 3 pathways were selected for analyzing the mechanisms of SBP for treating coronary heart disease.Conclusion: This study systematically illustrated the mechanisms of the SBP by analyzing the corresponding "drug-target-pathway-disease" interaction network.

Bufotenine and its derivatives:synthesis,analgesic effects identification and computational target prediction

Natural product bufotenine(5)which could be isolated from Venenum Bufonis,has been widely used as a tool in central nervous system(CNS)studies.We present here its quaternary ammonium salt(6)which was synthesized with high yields using 5-benzyloxyindole as raw materials,and we firstly discover its analgesic effects in vivo.The analgesic evaluation showed that compounds 5 and 6 had stronger effects on the behavior of formalin induced pain in mice.Moreover,the combination of compound 6 and morphine has a synergistic effect.We intended to explain the molecular mechanism of this effect.Therefore,36 analgesic-related targets(including 15 G protein-coupled receptors,6 enzymes,13 ion channels,and 2 others)were systemically evaluated using reverse docking.The results indicate that bufotenine and its derivatives are closely related to acetyl cholinesterase(AChE)orα_(4)β_(2) nicotinic acetylcholine receptor(nAChR).This study provides practitioners a new insight of analgesic effects.