QSPR/QSAR Studies With The Descriptors Derived From Electrostatic Potentials On Molecular Surface

Quantitative structure-property / activity relationships(QSPRs / QSARs) have been widely used in the fields of drug research and development,environment science,and material science.In the QSPR / QSAR studies,the choice of appropriate structural parameters plays a pivotal role.In previous QSPR studies,our research group have successfully applied and developed a set of structural descriptors derived from electrostatic potentials on molecular surface.The present thesis was devoted to the QSPR studies for somewhat complex systems and QSAR study by using this type of structural descriptors,together with some topological indices.It consists of three chapters,which can be summarized as follows:In the first chapter,QSPR / QSAR were first introduced.Then,molecular surfaces,electrostatic potentials on molecular surfaces as well as their parameterization were reviewed.Finally,research aim and scheme of the present thesis were put forward.In the second chapter,Ab initio calculations have been performed for all 197 organic compounds.On the basis of optimized structures,five kinds of topological indices,electrostatic potentials as well as their statistically-derived quantities have been obtained.Linear correlations between the human blood:air,human and rat tissue(fat,brain,liver,muscle,and kidney):air,rat blood:air,saline:air and oliver oil:air partition coefficients(denoted by log(Hb:a),log(Hf:a),log(Hbr:a),log(Hl:a), log(Hm:a),log(Hk:a),log(Hf:a),log(Rbr:a),log(Rl:a),log(Rm:a),log(Rk:a), logK(b:a),logK(s:a),logK(o:a),respectively) and the structural descriptors have been established by using multiple linear regression method.It appears that the quantities derived from electrostatic potentials,V_min,V_s,min,V_s,max,σ_<sup>2,σ_tot²,v,N_v^-,∑V_s,ind^-, together with the molecular volume and some popular quantum chemical descriptors (e.g.E_LUMO andμ) and 3D-MoRSE descriptors can be well used to express the quantitative structure-property relationships of organic compounds.The third chapter was devoted to the study of quantitative structure-activity relationship(QSAR) for indazolyl ureas as TRPV1 antagonists.First,QSAR study has been performed for 27 indazolyl urea compounds by using 1H-indazole tautomeric form in the molecular structure,a combination of structural descriptors derived from electrostatic potentials on molecular surface and topological indices, and multiple linear regression in the model construction.Then,using another tautomer(2H-indazole form),all of the above processes were repeated to investigate the effect of tautomerism upon the QSAR modelling.Three dimensional quantitative structure-activity relationship(3D-QSAR) studies have also been conducted for comparison.It has been shown that(1) tautomerism has a significant effect on the QSAR modelling,and the models obtained from 1H-indazol tautomeric form always represent higher quality than those from 2H-indazol tautomer,which indicates that 1H-indazol tautomer of the indazolyl urea is probably the active form when binding with the TRPV1 channel protein;(2) the theoretical descriptors derived from electrostatic potentials on molecular surface together with the GETAWAY descriptors can be well used to express the quantitative structure-activity relationship of indazolyl urea TRPV1 channel antagonists,and the results are superior to those with 3D-QSAR models.