3D-QSAR Study And Molecular Design Of Phenazine Compounds Against Human Small Cell Lung Cancer And Mycobacterium Tuberculosis

Many phenazine compounds have good anti-tumor and anti-tuberculosis activity.Computer aided drug design(CADD)can guide the rational design of the drug molecules,greatly reducing the workload of new drug R&D,shortening the lifecycle of development,and lowering the cost of R&D.CADD has been applied to the development of new drugs.Three-dimensional Quantitative Structure-Activity Relationship(3D-QSAR)is a kind of computer-aided drug design.3D-QSAR can combine mathematical and statistical methods to assist the relationship research of three-dimensional structural information of the molecule and its activity.And the model can be used to guide molecular design.Our laboratory focuses on the regulation mechanism of phenazine compound biosynthetic pathways,and optimization of the phenazine production in Pseudomonas secondary metabolites.The models can be used to screen compounds by predicting the activity of phenazines to guide the development of new phenazine drugs.This article built a 3D-QSAR model about the anticancer(NCI-H69)activity of phenazine compounds by Discovery studio 3.5.The five-fold cross-validation coefficient of the constructed 3D-QSAR model was q~2=0.531,the non-cross-validation coefficient was r~2=0.942,and the best principal component number was 3,and the model has good prediction ability.The model shows that the groups at position 2 with larger steric hindrance or stronger electropositive properties are conducive to the activity.The reduction in steric hindrance at position 3 is good to activity,and the enhancement of the positive charge at position 8 facilitates the increase of the activity.For longer branched chain at position 9,the stronger negative charge can give higher activity of the compoun.The 3D-QSAR model can guide the design of anti-small cell lung cancer compounds,and 6compounds with good activity were obtained.The model provides a new idea for the design and screening of phenazine antitumor drugs with faster time,lower workload and lower cost.This article also discusses the application scope of this model based on experiments of compound activity checking.Based on published data on the activity of phenazine compounds,this article built a 3D-QSAR model of phenazine compound against Mycobacterium tuberculosis H37Rv.The five-fold cross-validation coefficient of this model was q~2=0.700,and the external validation coefficient was r~2=0.903,the best number of principal components was 3,and the model has good application ability.For the longer branched chain at site No.3,the enhancement of negative charge of branched chain near No.3or the enhancement of positive charge of branded chain far away R3 are both good to activity.According to the 3D-QSAR model,four design compounds with good activities were obtained.The models established in this paper can predict the activity of phenazine compounds,and help screen the compounds with application value,and provide reference for the new biosynthesis of phenazine compounds.