Pharmacophoric Site Identification and Inhibitor Design for Autotaxin

Abstract

Autotaxin (ATX) is a potential drug target that is associated with inflammatory diseases and various cancers. In our previous studies, we have designed several inhibitors targeting ATX using computational and experimental approaches. Here, we have analyzed topological water networks (TWNs) in the binding pocket of ATX. TWN analysis revealed a pharmacophoric site inside the pocket. We designed and synthesized compounds considering the identified pharmacophoric site. Furthermore, we performed biological experiments to determine their ATX inhibitory activities. High potency of the designed compounds supports the predictions of the TWN analysis.

Benzoxaboroles—Novel Autotaxin Inhibitors

“…During the final preparation of the manuscript, the Kang group analyzed the topological water network in the binding pocket of ATX. Using this pharmacophoric insight, new molecules were synthesized and tested for their ATX inhibitory activities [23].…”

Small Molecule Inhibitors of DYRK1A Identified by Computational and Experimental Approaches

“…Our research group has developed and is optimizing algorithms for determining TWNs. In our previous study, we performed MD simulations on 26 kinases in aqueous solution and analyzed TWNs in their ATP binding sites [ 35 ]. Other previous studies used TWN analysis to study protein hydration [ 38 ], kinase selectivity [ 33 ], kinase inhibitor design [ 35 , 36 ], and drug repositioning [ 35 ].…”

“…Water molecules form water-ring networks through hydrogen bonds, which the authors have termed topological water networks (TWNs) [ 33 , 34 , 35 , 36 , 37 , 38 ]. These networks include small rings, such as trimers (R3), tetramers (R4), pentamers (R5), and hexamers (R6).…”

“…Our research group has developed an algorithm to determine topological water networks (TWNs) [ 33 , 34 ]. Previously, we used the TWN-based approach to investigate kinase selectivity [ 33 ], protein–ligand binding [ 34 ], and drug repositioning between kinases [ 35 ] to design kinase inhibitors [ 35 , 36 ], explore protein folding [ 37 ], and understand protein hydration [ 38 ]. In our previous report, 26 kinase-staurosporine complex structures were used for TWN analysis and staurosporine-based repositioning [ 35 ].…”

Structure-Based Design of Biologically Active Compounds

“…Londhe et al [ 4 ] analyzed four X-ray structures of keap1-Nrf2 inhibitors using molecular dynamics (MD) simulations and the path-based free energy method of umbrella sampling (US) for deriving amino acid residues involved in hydrophobic and electrostatic interactions useful for structure-based design of improved inhibitors. Lee et al [ 5 ] analyzed the binding pocket of autotaxin by molecular dynamics and investigated the role of the water molecules in the binding site through a topological water network (TWN) analysis. Based on the results of this analysis, they successfully designed and synthesized novel and potent autotaxin ligands.…”