Molecular dynamics simulation study of PTP1B with allosteric inhibitor and its application in receptor based pharmacophore modeling

Abstract

Allosteric inhibition of protein tyrosine phosphatase 1B (PTP1B), has paved a new path to design specific inhibitors for PTP1B, which is an important drug target for the treatment of type II diabetes and obesity. The PTP1B1-282-allosteric inhibitor complex crystal structure lacks alpha7 (287-298) and moreover there is no available 3D structure of PTP1B1-298 in open form. As the interaction between alpha7 and alpha6-alpha3 helices plays a crucial role in allosteric inhibition, alpha7 was modeled to the PTP1B1-282 in open form complexed with an allosteric inhibitor (compound-2) and a 5 ns MD simulation was performed to investigate the relative orientation of the alpha7-alpha6-alpha3 helices. The simulation conformational space was statistically sampled by clustering analyses. This approach was helpful to reveal certain clues on PTP1B allosteric inhibition. The simulation was also utilized in the generation of receptor based pharmacophore models to include the conformational flexibility of the protein-inhibitor complex. Three cluster representative structures of the highly populated clusters were selected for pharmacophore model generation. The three pharmacophore models were subsequently utilized for screening databases to retrieve molecules containing the features that complement the allosteric site. The retrieved hits were filtered based on certain drug-like properties and molecular docking simulations were performed in two different conformations of protein. Thus, performing MD simulation with alpha7 to investigate the changes at the allosteric site, then developing receptor based pharmacophore models and finally docking the retrieved hits into two distinct conformations will be a reliable methodology in identifying PTP1B allosteric inhibitors.

Loop 5-directed Compounds Inhibit Chimeric Kinesin-5 Motors

“…The second idea is that allosteric networks and control are conserved features in protein families (32). The fundamental question of whether site-to-site communication is conserved is one of therapeutic relevance, as allostery is a major consideration in drug design not only for the human Kinesin-5 proteins but for other protein families as well (33)(34)(35).…”

Novel Non-carboxylate Benzoylsulfonamide-Based Protein Tyrosine Phosphatase 1B Inhibitors with Non-competitive Actions

“…Several X-ray crystal structure analyses and computational simulations recently revealed the binding sites of allosteric inhibitors and the inhibitory mechanisms in which a small molecule binds to allosteric sites and stabilizes the conformation associated with the inactive state of PTP1B. [37][38][39][40][41][42][43][44] Based on the molecular similarities between our compound 18K and an allosteric inhibitor bound to PTP1B (Fig. 2a), we constructed a structural model of the 18K-PTP1B complex by molecular alignment of the compounds, followed by validation and refinement of the structure obtained using a molecular dynamic (MD) simulation.…”

Protein tyrosine phosphatase 1B inhibitory activity of alkaloids from Rhizoma Coptidis and their molecular docking studies

“…This allosteric site makes these inhibitors highly selective for PTP1B. The allosteric inhibitor may act by stabilizing the conformation that precludes the closure of the WPD loop (Kamerlin et al, 2007;Bharatham et al, 2008). Bialy and Waldmann (2005) reported that noncompetitive or allosteric inhibitors might oxidize the catalytic cysteine (Cys215).…”