Applications Of Quantum Chemistry Methods In The Calculation Of Physical,Chemical,Biological Properties Of Compounds

Quantum chemistry is an important theory in chemoinformatics,which can,in principle,express all the electroni(?) and geometric properties of molecule accurately. But it was restricted by the studied system and the time of calculation.In this thesis, the quantum chemistry calculation was combined with the quantitative structure-activity /property relationship(QSAR/QSPR),in other words,models combining the two different types of learning methods(deductive and inductive) in chemoinformatics were developed to predict the physico-chemical,biochemical and pharmacological properties of compounds.Using this efficient approach,it can be used to find successful structure-activity/property correlations and then predict the activity or property of other compounds more accurately.At the same time,it can accelerate the proccss for the development of cffective models to design new molecules like drugs,materials.In this thesis,the following studies were carried out:Chapter 1:A brief description of quantum chemistry and quantitative structure-property/activity relationship(QSAR/QSPR) was introduced,including their basic concept and recent progress.Chapter 2:A QSPR model was developed for the drug permeability ot 56 compounds,including benzoic acids,pyridines and quinolines.The multiple linear regression(MLR) method was used to build QSPR models based on four descriptors selected by genetic algorithm(GA) using training set samples.Very good result was obtained,for the training set,R²=0.94,Q²=0.91,F=151.36,RMSE=0.22, AARD=10.21%.For the test set,the model gave R²=0.92,RMSE=0.26, AARD=13.29%.By analysis the influence of compounds' structure on drug permeability,we obtained some useful information which would be very useful in the design of potential drugs with desired permeability.Chapter 3:In this work,an accurate and validated quantitative structure-activity relationship(QSAR) model was developed for the caspase-mediated apoptosis-inducing effect of 52 substituted phenolic compounds in a murine leukemia cell line(L1210).All molecules were respectively optimized by the density functional theory(DFT) and semi-empirical method to obtain the lowest energy conformations. The whole data set was divided into representative training and test sets using DUPLEX method.Then multiple linear regression(MLR) method was used to build QSAR models based on the descriptors selected by genetic algorithm(GA) using training set samples.The built models were rigorously validated both internally and externally.The obtained model based on DFT optimized geometry is better than that based on semi-empirical optimized geometry and the published work with the correlation coefficient(R²) of 0.938 for the training set and 0.939 for the test set.The result is discussed in the light of the main features that influence the inducing activity of caspase-mediated apoptosis.Density Functional Theory(DFT) is a precise method, which can give the electronic structure of compounds accurately.Combining DFT calculation with QSAR analysis not only overcomes the shortcomings of traditional QSAR effectively,but also expands the traditional scope of application of QSAR.Chapter 4:Three Density Functional Theory methods(B3LYP,B3PW91 and B3P86) with the 6-31G(d) and 6-311++G(d,p) were used to study the conformation and homolytic Y-NO₂(Y=N,O) bond dissociation energies(BDE) of the three types nitro-containing compounds.It is found that at the site of Y-NO₂ there is only one stable conformation for N-Nitrosulfonamides and O-Nitro alcohols,whereas there are two stable conformations for N-Nitroacylamides and the anti-conformation is favored because of the steric effect.By comparing the computed energies and experimental results,it is noted that different quantum chemical calculational methods are suitable for different molecular systems,B3P86/6-311++G(d,p) provides for N-Nitrosulfonamides,B3LYP/6-311++G(d,p) gives similar BDE with experiment for N-Nitroacylamides and O-Nitro alcohols.Subsequently,the substituent effects on the BDE of the Y-NO₂ bond for three types compounds are further analyzed,the result shows that the electron donating groups are bond-strengthening,whereas electron withdrawing groups are bond-weakening,though for N-Nitrosulfonamides and N-Nitroacylamides,there is a stronger correlation between the substituent electronic effects and the stability of the radical product than that of O-Nitro alcohols. Chapter 5.Owing to the more BDE values of peroxides which is an important type compounds in troposphere,a fast and relatively method was developed for the prediction BDE of O-O bond of 110 peroxides.By this method,a raw BDE value was obtained from the optimized geometry at DFT,and then an accurate BDE values was obtained by GA procedure.The final model is a five-parameter linear equation and is validated by a leave-one-out cross-validation.Calculated results demonstrated that the QSPR calibration lead to a remarkable reduction of RMSE and AARD:the RMSE is reduced from 10.88kcal/mol to 2.42kcal/mol,the AARD reduced from 9.45%to 5.66%.Comparison of the results by B3LYP/6-31G(d,p) revealed that B3LYP/6-31G(d,p) in combination with a GA calibration is reliable in the accurate prediction of BDE of O-O bond of peroxides.The idea that combining the quantum chemistry calculations and GA calibration would extend to predicting other types BDE in theory methods.