The Structure-activity Relationship And Interaction Of The New Anti-tumor TNBG And Its Derivatives

In this paper, computer aided drug design (CADD) is used to study thequantitative structure-activity relationship (QSAR) of the new anti-cancerdrug Tetrazanbigen and its derivatives (TNBGs) and the interaction betweenTNBGs with PPARγ. This study can be used to guide structural optimizationof TNBG and provide a theoretical basis and guidance for designingefficient non-cytotoxic anti-cancer drugs. The major works are as follows:1. Quantitative structure-activity relationship for TNBGs was studiedbased on MEDV-4and H-MEDV in this paper. The2D-QSAR models wereconstructed by multiple linear regression (MLR) and stepwise multipleregression (SMR).The H-MEDV model showed better performance inpredictability and reliability than that of MEDV-4. The correlationcoefficient (R) of H-MEDV is0.862. Crossvalidation was performed byleave-one-out procedure (LOO) and the correlation coefficient is0.713.2.3D-QSAR model was constructed by CoMFA. Cross-validation (CV)correlation coefficient q2is negative.3. The molecular docking method was used to make the combinationTNBGs and PPARγ receptor, all moleculars can be combinate with PPARγ, and the the initial conformation of complex structure can be attained.Molecular dynamics (MD) showed all TNBGs can be combined withhydrophobic region of PPARγ Y type binding cavity, formed hydrophobicinteractions, van der Waals forces, and cation-pi interactions with aminoacids such as LEU228, CYS285, ARG288, LEU330, VAL339, LEU340,ILE341, SER342, MET364, etc.4. MM-PBSA method calculated binding free energy of TNBGs withPPARγ for the MD results，van der Waals forces, polar solvation energyand electrostatic interaction constitute of the binding energy. The bindingfree energy and the activity have a poor correlation, it verified the view thatTNBGs are multi-target antineoplastics.