Yellapu Nanda Kumar, Kilaru Ravendra Babu, Chamarthi Nagaraju, Pvgk Sarma, Matcha Bhaskar
Division of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati, 517 502, Andhra Pradesh, India; Biomedical Informatics Centre, Vector Control Research Centre, Indian Council of Medical Research, Pondicherry, India.
Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India.
Comput Biol Chem. 2017 Jun;68:118-130. doi: 10.1016/j.compbiolchem.2017.02.011. Epub 2017 Mar 2.
Glucokinase (GK) is a potential therapeutic target of type 2 diabetes and GK activators (GKAs) represent a promising class of small organic molecules which enhance GK activity. Based on the configuration and conformation of the allosteric site of GK, we have designed a novel class of amino phosphonate derivatives in order to develop potent GKAs. The QSAR model developed using numerous descriptors revealed its potential with the best effective statistical values of RMSE=1.52 and r=0.30. Moreover, application of this model on the present test set GKAs proved to be worthy to predict their activities as a better linear relationship was observed with RMSE=0.14 and r=0.88. ADME studies and Lipinski filters encouraged them as safer therapeutics. The molecular dynamics and docking studies against the GK allosteric site revealed that all GKAs bind with best affinities and the complexes are strengthened by H-bonding, phosphonate salt bridges, hydrophobic and arene cat ionic interactions. Finally, in vitro evaluation with human liver GK revealed their potential to increase the GK activity by different folds. The results from QSAR, ADME, molecular docking and in vitro assays strongly suggested that the present molecules could be used as effective and safer therapeutics to control and manage type 2 diabetes.
葡萄糖激酶（GK）是2型糖尿病的一个潜在治疗靶点，而GK激活剂（GKAs）是一类有前景的小有机分子，可增强GK活性。基于GK变构位点的构型和构象，我们设计了一类新型氨基膦酸酯衍生物，以开发强效GKAs。使用众多描述符建立的QSAR模型显示了其潜力，RMSE = 1.52和r = 0.30的最佳有效统计值。此外，将该模型应用于当前测试集的GKAs时，被证明值得用来预测它们的活性，因为观察到了更好的线性关系，RMSE = 0.14和r = 0.88。ADME研究和Lipinski筛选表明它们是更安全的治疗药物。针对GK变构位点的分子动力学和对接研究表明，所有GKAs都以最佳亲和力结合，并且复合物通过氢键、膦酸盐盐桥、疏水和芳基阳离子相互作用得到加强。最后，用人肝GK进行的体外评估显示它们有潜力以不同倍数增加GK活性。QSAR、ADME、分子对接和体外试验的结果强烈表明，当前的分子可作为有效且更安全的治疗药物用于控制和管理2型糖尿病。
