Studies Of The Inhibitor Binding Process On PTP1B And The Screening Approach

Researchers and pharmaceutical companies are facing with the increasing costs of research and development and the decreasing varities of new drugs in drug development and manufacturing process, where computer aided drug design approach can be utilized to reduce the cost of research and development at the initial stage of pharmaceutical process, meanwhile, can provide active compounds for subsequent clinical research. This study regard Protein tyrosine phosphatase 1B (PTP1B) as target for preliminary drug development research. PTP1B inhibitors are potential therapeutic agents in treating Type II diabetes and obesity. In this study, molecular dynamics simulation, binding free energy calculation, similarity searching and virtual screening were used 1) to study the binding modes and the inhibition differences between Trivaric Acid and Nordivaricatic Acid; 2) to investigate the binding mechanism; and 3) further to find novel efficient inhibitors with the aids of drug-like compound database screening. The results are described as follows.(1) The inhibition difference of Trivaric Acid and Nordivaricatic Acid was studied using molecular dynamics simulations and MM/GBSA binding free energy calculations. The MM/GBSA binding free energies for these two complexes are -28.53 kcal/mol for Trivaric acid and -21.74 kcal/mol for Nordivaricatic acid, which is consistent with the experimental IC50 values 0.036 pmol/L (Trivaric) and >50 μmol/L (Nordivaricatic). In the molecular dynamics simulation, Trivaric Acid has interactions with the main binding site, the second binding site and the linker region with a binding free energy higher than that of Nordivaricatic Acid which is graduately moving away from the original binding site. This explains why Nordivaricatic Acid can not inhibit PTP1B.(2) Among the eight molecules obtainded from similarity searching based on Trivaric Acid, some molecules with only the ether group or the carbonyl group can not provide efficient interaction so that these molecules will move out of the main binding site during the molecular dynamics simulation running. Other molecules can provide their carboxyl or ester group as the hydrogen bond acceptor to form strong hydrogen bond interactions with the main active site residues. The best bound compund ZINC73815976 possesses a fragment which plays an important role in the binding and can be used as a molecular block for the next step drug design. (3) A virtual screening over 500,000 drug-like compounds in the ZINC database was performed and 10 hits have be chosen. The structures of the 10 hits and their binding modes all provide strong intermolecular interaction including efficient hydrogen bonds using their carboxyl, or hydroxyl, or sulfone groups. In addition, their aromatic ring can form π-π stacking with Phe182 to increase the binding affinity. Their amide as a hydrogen bond donor can interact with the oxygen atoms of Gln262 and Asp48 in the linker region. Most hits provide their hydrogen bond acceptor or aromatic ring to form hydrogen bond and cation-π interactions with Arg24 and Arg254 in the second binding site.This study reports a set of suitable compounds for drug research and development of PTP1B inhibitors based on virtual screening and molecular dynamics simulation, contributing to the subsequent design and characterization in the experiment and promotes research on the treatment of Type Ⅱ diabetes.