Molecular docking, 3D-QSAR,molecular dynamics,synthesis and anticancer activity of tyrosine kinase 2 (TYK 2) inhibitors

Abstract

A therapeutic rationale is proposed by selectively targeting tyrosine kinase 2 (TYK 2) to obtain potent TYK 2 inhibitors by molecular modeling studies. In the present study, we have taken tyrosine kinase (TYK 2) inhibitors and carried out molecular docking, 3?D quantitative structure–activity relationship (3D-QSAR) analysis and molecular dynamics (MD). Based on the 3D-QSAR results thirteen new compounds (R-1 to R-13) were designed and synthesized in good yields. The synthesized molecules were evaluated for their in vitro anticancer activity against LnCap and A549 cell lines. The molecules R-1, R-3, R-5, R-7, and R-10 exhibited considerable anti cancer activity.     

化合物毒性及三维结构参数的定量构效关系研究

目的：建立小分子化合物毒性的三维定量构效关系模型,探索化合物毒性数据和三维结构参数之间关系的方法。方法：利用比较分子力场分析方法（CoMFA）,建立了一组对发光菌有急性毒性的小分子的三维定量构效模型。结果：模型的交叉验证相关系数q^2=0．731,非交叉验证相关系数r^2=0．973,标准偏差SE=0．122,F=70．910。结论：该模型具有较好的预测能力,表明在甲基的邻对位减小取代基体积或电负性可以降低化合物毒性。     

CoMFA and CoMSIA studies on fluorinated hexahydropyrimidine derivatives

3D-QSAR models of a series of fluorinated hexahydropyrimidine derivatives with cytotoxic activities have been developed using CoMFA and CoMSIA. These models provide a better understanding of the mechanism of action and structure–activity relationship of these compounds. By applying leave-one-out (LOO) cross validation study, the best predictive CoMFA model was achieved with 3 as the optimum number of components, which gave rise to a non-cross-validated r² value of 0.978, and standard error of estimate of 0.059, and F value of 144.492. Similarly, the best predictive CoMSIA model was derived with 4 as the number of components, r² value of 0.999, F value of 4381.143, and standard error of estimate, 0.011. The above models will inspire the design and synthesis of novel hexahydropyrimidines with enhanced potency and selectivity.     

Structure-activity relationship analysis of 3-phenylpyrazole derivatives as androgen receptor antagonists

Abstract

Prostate cancer (PCa), an epithelial malignancy that occurs in the prostate, reminds the second leading cause of cancer-related incidence in men worldwidely. Androgen receptor antagonists are the main therapeutic strategy of PCa, which can block the binding of androgen to androgen receptors. However, the long-term treatment of marketed anti-androgens in patients can inevitably cause drug resistance problem. The research of searching for new drugs with novel skeleton is always on the way. Recently, a series of 3-phenylpyrazole derivatives were reported to antagonize the function of AR, but their efficiencies are not good enough and need to be improved. In this work, comparative molecular field analysis and comparative molecular similarity indices analysis methods were employed to study the structure activity relationships of these derivatives. Two different methods were used to obtain the optimal molecular conformation alignments, one is based on atomic alignment and the other is based on molecular docking. The final result shows that both these two strategies can obtain satisfactory results and the atomic alignment performs a little better than docking. The models illustrate the key structural features highly related with the androgenic bioactivity and provide valuable suggestions for the design of new androgen receptor antagonists in future.

Communicated by Ramaswamy H. Sarma     

Structural exploration of tetrahydroisoquinoline derivatives as HDAC8 inhibitors through multi-QSAR modeling study

Abstract

Histone deacetylase 8 (HDAC8) is one of the crucial HDACs responsible for influencing the epigenetic functions of the body. Overexpression of HDAC8 is found to be involved in numerous disease conditions such as tumorigenesis, cell proliferation, cancer, viral infections, neuronal disorders and other epigenetic diseases. Therefore, inhibition of HDAC8 is a primary method to combat these diseases. In this article, a multi-QSAR modeling study on tetrahydroisoquinoline derivatives was conducted to identify important contributions of the structural features of these compounds toward HDAC8 inhibition. All these QSAR modeling techniques were individually validated and justified the observations of each other. The results implied that the tetrahydroisoquinoline moiety may be effective as a cap group than as a linker moiety for HDAC8 inhibition. Different substitutions at the tetrahydroisoquinoline scaffold were also found to be crucial in modulating HDAC8 inhibition.

Communicated by Ramaswamy H. Sarma