Computational protocol: Virtual screening, optimization, and identification of a novel specific PTP-MEG2 Inhibitor with potential therapy for T2DM

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Protocol publication

[…] Structure-based virtual screening in ZINC drug-like database was performed in silicon. The structure database was prepared by Schrödinger's LigPrep 2.3 and virtually screened using Schrödinger's Glide 5.5, which incorporated Maestro 9.2 of RHEL 5.0. The docking pocket of PTP-MEG2 for virtual screening was identified by the Receptor Grid-generation tool of Schrödinger, a grid within 5Å from original ligand (B26) in its co-crystal structure (PDB ID: 4GE6).The increased selectivity of novel inhibitors was introduced in several continuous stages of scaffold optimization by a core-hopping [, ] program embedded in Schrödinger Suite 2012. ZINC fragments database [] was used. All investigated compound candidates were docked into the binding pocket through the flexible docking model. According to the docking scores [, ], top candidates with rational structures were classified as potential PTP-MEG2 inhibitors for further study. [...] The “QikProp”[] module predicted ADME (absorption, distribution, metabolism, and excretion) properties. The parameters of the partition coefficient (QP logPo/w), van der Waals surface area of polar nitrogen and oxygen atoms (PSA), predicted aqueous solubility (QP logS), and apparent MDCK permeability (QPP MDCK) were used in the QikProp to evaluate the acceptability of the compounds []. [...] The interaction between compound 4a and PTP-MEG2 was predicted by Glide 5.0 of Schrodinger 2012, a commonly used method for docking studies. Crystal structure of PTP-MEG2 (PDB ID: 4GE6) was downloaded from the PDB bank. As a potential inhibitor against PTP-MEG2, compound 4a was prepared in silicon via the ligand structure preparation module “LigPrep”. Docking site was determined by original ligand of PTP-MEG2 in its crystal structure. [...] Molecular dynamics simulation is a tool used to study the interaction between small molecules and proteins. In this study, we combined the static structures and dynamic information to investigate the binding mode and affinity between PTP-MEG2 and its inhibitors. We used GROMACS 4.5 [] for Linux for molecular dynamics simulation.The topology file, partial charges and force field parameters for ligand atoms were generated by the Dundee PRODRG 2.5 Server (University of Dundee, Dundee, Scotland) (beta) []. Taking PTP-MEG2 as an example, the simulation system was solvated in a specific box with SPC water solute [, ] and sodium and chloride ions were added into the system to neutralize redundant charges. Steepest descents approach was used to minimize energy for the system until reaching a tolerance of 100 kcal/mol. A 40 ns molecular dynamics simulation [, ] was performed with a time step of 1 fs, and the corresponding coordinates were stored every 100 fs. All simulations were performed under constant temperature (310 K), periodic boundary conditions and NVT ensembles. […]

Pipeline specifications

Software tools LigPrep, QikProp, Glide, GROMACS, PRODRG
Applications Drug design, Protein interaction analysis
Diseases Diabetes Mellitus
Chemicals Silicon, Tyrosine