Computer Aided Structural Design And Toxicity Study Of Novel Compounds For Anti-prostate Cancer

Objective:Globally,the incidence and mortality of prostate cancer rank second and fifth in male tumors,respectively.Castration-resistant prostate cancer is difficult to treat and is prone to cancer metastasis.Therefore,the development of new drugs is of great significance for the treatment of prostate cancer.In this paper,two types of compounds with anti-prostate cancer activity were studied by three-dimensional quantitative structure-activity relationship?3D-QSAR?,molecular docking and toxicity prediction studies,which provide ideas and theoretical guidances for designing and developing low toxicity and high activity new anti-prostate cancer compounds.Methods:In this work,two types of compounds with anti-prostate cancer activity were studied by computer-aided drug design methods.Firstly,3D-QSAR method was used to construct the computational model,and discuss the important structural factors affecting the activity of compounds.Then the molecular docking method was used to study the active sites,dominant conformations and bind situation of the compounds in proteins.And the mechanisms of interaction between ligands and proteins were discussed.Based on the above studies,novel compounds with anti-prostate cancer activity were designed.We initially screened the compounds by activity prediction and molecular docking results.Finally,using the computational toxicology method,the mutagenicity,tumorigenicity,irritating toxicity,reproductive toxicity and drug-like properties of selected compounds were predicted and analyzed.Results:1.3D-QSAR study was performed on 34 curcumin analogues,and a reliable3D-QSAR model with strong predictive ability was established by using the comparative molecular similarity index analysis?CoMSIA?method(q²=0.540,R²=0.984,SEE=0.063,F=258.377,R²_boot=0.993,SEEboot=0.040,R_p²=0.703).The relationship between structures and activity of compounds was obtained by analyzing the contour maps.Combined with the results of molecular docking,we designed 186 novel compounds,predicted their activity,and selected 10 compounds with the best activity.In addition,these 10 compounds were predicted and analyzed for toxicity and drug-like properties using the software OSIRIS Property Explorer.Based on a comprehensive analysis of the above experimental results,we believe that new compound 4i is the optimal structure.2.Based on 3D-QSAR and molecular docking methods,62 flavonols were studied.The3D-QSAR model was constructed basis on the structure and activity of the compounds.3D-QSAR applied the comparative molecular force field?CoMFA?and CoMSIA method.The two models were proved to be reliable and have strong predictive ability(CoMFA:q²=0.520,R²=0.989,SEE=0.067,F value is 348.091,R²_boot=0.995,SEE_bootis 0.046,R_p²=0.677;CoMSIA:q2=0.367,R2=0.977,SEE=0.097,F value is 182.406,R²_{bo ot}=0.988,SEEboot=0.069,R_p²=0.704).118 new compounds with anti-prostate cancer activity were designed by analyzing the results of contour maps and molecular docking,then the activity of the compounds was predicted.The 9 highest activity compounds were screened.The 9new compounds were evaluated for mutagenicity,tumorigenicity,irritating toxicity,reproductive toxicity and drug-like properties by OSIRIS Property Explorer.Based on a comprehensive analysis,17050^thh and 17064^thh compounds were recommend for further studies.Conclusion:Two kinds of compounds with anti-prostate cancer activity were systematically studied by 3D-QSAR and molecular docking methods.Based on the research results,new compounds with higher activity were designed,and the toxicity risk of the compounds was predicted.The results showed that compounds 4i,17050 and 17064 were novel compounds with high activity and low toxicity risk,which deserve further study.It provides new ideas and theoretical basis for the development of low toxicity and high activity anti-prostate cancer drugs.