Chemical Space Analysis Software And Web Development And Its Application In The Design Of NA Inhibitors

With the development of drug screening technology,drug development data has grown exponentially,involving molecular structure,activity,physicochemical properties,toxicity,targets,genes,pathways and other multi-dimensional information.The chemical space and dimensions of these medical big data are increasing,which brings great opportunities and challenges to drug data analysis and visualization.In order to find the active small molecules for drug research from these spaces,it is necessary to use a variety of analysis and visualization methods to focus from different angles to smaller spaces for research.Therefore,this paper developed a chemical space analysis and visualization tool to assist drug design.The specific research contents are as follows:（1）Chemical space analysis and visualization software and Web server developmentBased on the open source HighCharts and vis.js charting plug-ins,we have developed Python visualization toolkits easyHighcharts and easyVisjs that can process/display chemical information according to the requirements of chemical space analysis;developed a modular chemical space analysis Python toolkit pyChemspace to implement compound libraries analysis and visualization of physicochemical properties,molecular structure and fragment information;to further reduce the barrier for drug developers to analyze chemical space,based on the above research,developed chemical space interactive analysis and visualization Web server IChemSpace（http://mwxiao.com/ichemspace）.（2）Chemical space analysis of influenza neuraminidase inhibitorsNeuraminidase（NA）is an important target for anti-influenza.Influenza neuraminidase inhibitors（NAIs）reported in the literature were collected,and chemical space analysis of NAIs was performed using IChemSpace.The results show that the physical and chemical parameters of NAIs are different from the physical and chemical parameters of general drugs.The range of hydrogen bond donors and hydrogen bond acceptors is relatively wide,and the values are relatively large.This may be because the active cavity of influenza neuraminidase is a polar active cavity,and the introduction of an appropriate amount of polar groups facilitates binding to the target protein NA;molecular skeleton analysis results indicate that the chalcone and flavonoids tructure in the natural product are good molecular skeleton of NA inhibitory activity;BRICS fragment analysis shows that amino,acetyl,carboxyl,isopentyl,polyphenol,and the like may be good NA inhibitory groups;The use of these fragments to design NA inhibitors has certain reference significance.（3）Design,synthesis and NA inhibitory activity of 5-benzylidene-4-oxothiazolidine derivativesCombining chemical space analysis,molecular docking,CoMFA and other methods to study the structure-activity relationship of the thiazolone-based NA inhibitors in our previous study.The results indicate that the electron-rich group with a small steric hindrance at the 5-position of the parent thiazole is advantageous for the activity.Some small active fragment rich in oxygen and nitrogen such as carboxyl group,ester group,nitro group or sulfhydryl group may be introduced to investigate the influence of the type and size of the group on the activity at this position;and the substituent on the benzylene benzene ring may preferentially introduce a small steric hindrance and hydrophilic group.Based on this,14 intermediates 4-oxothiazolidine（C1-C14）and 52 5-benzylene-4-oxothiazolidine derivatives（D1-D52）were synthesized and evaluated its NA inhibitory activity;The structure-activity relationship analysis of the mother nucleus was carried out,and the following main conclusions were obtained:C4 has the best NA inhibitory activity,IC₅₀ is 33.60μM;After the replacement of the thiazole ring with the oxazole ring,the activity was significantly reduced;after S was replaced by Se on the thiazolinone ring,the activity was significantly reduced;the 4-position of the thiazole had the greatest influence on the activity of the mother nucleus,and the activity of the isopropyl(IC₅₀=33.60μM)is superior to methyl(IC₅₀=53.41μM)and n-propyl.The activity of the product after introduction of the benzylidene group at the 5-position of the thiazolinone ring is higher than that of the corresponding starting material;the compound with the best activity is D18,the IC₅₀ value is 13.06μM,and the activity values of D15,D16,D25,D38,D53,D56,D59 and D67 are better than those in the previous study;by comparing the activity changes before and after the modification of each series of compounds,it was found that the different substituted thiazolinone rings were introduced into 4-CO₂H,4-OH,3-OCH₃-4-OH substituted benzylidene groups.Further structure-activity relationship analysis indicated that the thiazolinone ring and the ferulic acid fragment are essential NA inhibitory active fragments of such compounds.