.5,6 - Dihydro - (9h) - Pyrazole [3,4-c] - 1, 2,4 - Triazolo [4,3-a] Pyridine Inhibitor And Quantitative Structure Of The Hsv-1 Inhibitors Effect Relationship

Quantitative structure-activity relationship(QSAR) study has been widely used for prediction of various physicochemical properties and biological activities of organic compounds by different statistical methods and various kinds of molecular descriptors.QSAR is an active research field worldwide,a frontal task in agricultural chemistry,biology,environmental chemistry and medicinal chemistry,especially in environmental toxicological evaluation and computer-aided drug design.QSAR is gaining popularity and wide applications.This thesis introduced comparative molecular field analysis,comparative molecular similarity indices analysis and hologram quantitative structure-activity relationship analysis to study the structure-activity relationships of 5,6-dihydro-(9H)- pyrazolo[3,4-c]-l,2,4-triazolo [4,3-a]pyridine inhibitors and herpes simplex virus 1(HSV-1) inhibitors,respectively.And finally we found out the important factors determining the activity,which is very helpful for structure modification and discovery of new active compounds.In the first chapter of the paper,a review of QSAR method,progress and applications is presented.In chapters 2 and 3 of the thesis,to study the relationship between the bioactivity and structure parameters of a series of 5,6-dihydro-(9H)-pyrazolo [3,4-c]-l,2,4-triazolo[4,3-a]pyridine inhibitors,two- and three-dimensional QSAR models were established by using comparative molecular field analysis (CoMFA) method and hologram quantitative structure-activity relationship method (HQSAR).The CoMFA method showed that the cross-validated coefficient q~2 was 0.565,the non-cross-validated r~2 was 0.867,the standard deviation SE was 0.362 and F was 49.782,the contributions of steric and electrostatic fields to bioactivity were 72.7%and 27.3%respectively.The best HQSAR model showed that the cross-validated coefficient q~2 was 0.628,the non cross-validated r~2 was 0.930,the standard deviation SE was 0.277.The influence of hologram length,fragment size and distinction parameters on the quality of HQSAR model was considered.Both of the model have good predictive ability,to increase the bulk of substituent or reduce the negative charge of substituent can increase the bioactivity.It is useful to insight into the further design of highly active compounds.In chapter four,two- and three-dimensional quantitative structure-activity relationships have been studied on a series of simplex virus 1(HSV-1) inhibitors by comparative molecular field analysis(CoMFA),comparative molecular similarity indices analysis(CoMSIA),and hologram quantitative structure-activity relationship (HQSAR).Different alignments were used in order to investigate the effects on the CoMFA and CoMSIA models.Different combinations of fields and different fragment parameters were also applied to explore the effects on the CoMSIA and HQSAR models.For the best CoMFA model.The q~2 value was 0.669 with principal components of 6,the noncross- validated squared coefficient was 0.953,The estimated F value is 94.011 and the standard error SE is 0.140.The contributions of the steric,electrostatic were 78.7%and 21.3%,respectively.It can be concluded that the activity of these inhibitors was mainly dependent on the steric and electrostatic. For the best CoMSIA model with the optimal number compotent of 6,q~2 of 0.693 and R~2 of 0.919,The estimated F value is 94.011 and the standard error SE is 0.183.The contributions of the steric,electrostatic and the hydrogen bond acceptor were 37.0%,41.9%,and 21.1%,respectively.It can be concluded that the activity of these inhibitors was mainly dependent on the steric,electrostatic and hydrogen bond acceptor.The comparison of the contributions of the three fields suggests that the hydrogen bond acceptor interactions play a very important role in the interactions between the ligands and the HSV-1 recptor.For the HQSAR method,the fragment types distinction of combination atom(A),bonds(B),connections(Co),hydrogen(H), chirality(Ch),donor and acceptor(DA)resulted in the best model.The q~2 value was 0.619 with principal components of 6,the noncross- validated squared coefficient was 0.921,standard error is 0.181.Three QSAR methods are used from this study should be very helpful in studying the relationship between the bioactivity and structure. Results indicate that structural replacements by small steric volumes and electron-withdrawing groups in the R2,R3 region are necessary to increase the HSV-linhibitors activity.In addition,this study also reveals how individual atom affect the molecular bioactivity.Three different models should be useful for further structure modification and discovery new potential HSV-linhibitors.