Quantitative structure–activity relationship study using genetic algorithm–enhanced replacement method combined with molecular docking studies of isatin derivatives as inhibitors of human transglutaminase 2

Abstract

Inhibition of the enzyme human transglutaminase 2 (TG2) is important for the treatment of various diseases. Isatin derivatives, including 3-acylidene-2-oxoindoles, inhibit of human TG2. In this work, quantitative structure-activity relationship (QSAR) and molecular docking studies were performed on the inhibitory activity of isatin derivatives. First, genetic algorithm (GA) was used for selecting the sum of descriptors. Then a small number of descriptors were selected using the enhanced replacement method (ERM) and the stepwise (SW) method. The descriptors nCl, HE, R4m+, and n = CHR were selected using GA-ERM and the descriptors R6m, R5e +, n = CHR, and HE were produced using the GA-SW method. Two linear and nonlinear methods, namely multiple linear regression (MLR) and support vector regression (SVR), were used for QSAR modeling. GA-ERM outperformed in combination with the SVR method, which indicated more power at the prediction of inhibitory activity. Also, molecular docking studies were performed for understanding the mechanism of interaction of isatin derivatives with TG2 and investigating the effect of some descriptors such as the hydration energy (HE) on the inhibitory activity of the studied compounds. Docking results revealed that the formation of hydrogen bonding and hydrophobic interactions play important roles in the connection between the protein TG2 (PDB: 3S3P) and isatin derivatives.enhanced replacement method, genetic algorithm, isatin, transglutaminase 2, molecular docking, quantitative structure-activity relationship (QSAR), support vector regression

In silico studies of the open form of human tissue transglutaminase

“…Compounds tested as tTG inhibitors at the moment of this study, according to the ChEMBL database (with up to 500 Standard Value), are listed in Table S1.1. Notably, previous in silico studies of tTG inhibitors relied on unveri ed molecular docking, therefore providing imprecise binding a nity data [17].…”

In silico studies of the open form of human tissue transglutaminase

“…Compounds tested as tTG inhibitors at the moment of this study, according to the ChEMBL database (with up to 500 Standard Value), are listed in Table S1.1 . Notably, previous in silico studies of tTG inhibitors relied on unverified molecular docking, therefore providing imprecise binding affinity data 25 , 26 .…”