QSAR And QSSR Study On Protein Tyrosine Phosphatase-1B Inhibitors-benzotriazole Derivatives

PTP-1B has recently received much attention as a potential drug target in type 2 diabetes, and selective PTP-1B inhibitors could be of significant therapeutic utility. Several groups have reported structurally diverse PTP-1B inhibitors with a good selectivity profile over other PTPs, but generally not over TCPTP. Because TCPTP has an 80% homology to PTP-1B in the catalytic domains, and non-selective inbition gives rise to severe side effects. Benzotriazole derivatives were found to be potent PTP-1B inhibitors, and provide a moderate degree of selectivity for PTP-1B over TCPTP. Molecular docking studies were performed using FlexX in order to find the different molecular mechanism between PTP-1B and TCPTP. The 3D-QSAR and 3D-QSSR studies were conducted by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA), and provied the useful information to improve the inhibitory activity and selectivity. Based on the docking conclusions, the hydrogen bond formed between Arg24 in PTP-1B and the molecular is of great importance to enhance the selectivity. The obtained models with the best predictions showed that bulky, negatively charged and hydrogen-bond donor groups at R2 position would increase the inhibitory activity, and bulky, positively charged and hydrogen-bond acceptor groups at the end of the R2 position would increase the selectivity. Sum of the above conclusions, the substitute which could increase inhibitory activity did not necessarily increased the selectivity. Therefore, we must consider all the factors to design new benzotriazole derivatives as PTP-1B inhibitors in future.