Building TIPE2 Inhibitors from Quadrant System for Fragment-Based Docking
TL;DR
It is demonstrated that quadrant-based fragment docking provides an effective strategy for designing inhibitors targeting proteins with large binding cavities and provides promising lead compounds for the development of TIPE2 inhibitors.
Abstract
Chronic inflammation is closely associated with cancer progression through the promotion of angiogenesis and tumor-supportive signaling pathways. Tumor necrosis factor-α–induced protein 8-like 2 (TIPE2) regulates leukocyte polarization through phosphoinositide transport and represents a promising therapeutic target for solid tumors. However, the large hydrophobic cavity of TIPE2 presents a significant challenge for inhibitor design. In this work, a quadrant docking grid system was developed to enable fragment docking in defined regions of the binding cavity, facilitating fragment linking with minimal overlap and maximal spatial coverage. To our knowledge, this is the first application of a quadrant grid docking strategy for fragment-based inhibitor design. Fragments were screened using AutoDock Vina 1.2.3 and selected based on both binding affinity and predicted aqueous solubility. The highest-binding linked compounds, F1-F12 and F1-F13, exhibited binding affinities of −12.4 and −11.5 kcal mol−1, respectively. Rational modifications yielded compounds MF112 and MF113 with improved predicted ADME properties while maintaining strong binding affinities of −11.7 kcal mol−1. Molecular dynamics simulations demonstrated stable binding complexes over 5 ns trajectories, with RMSD stabilization after approximately 1–2 ns. These results demonstrate that quadrant-based fragment docking provides an effective strategy for designing inhibitors targeting proteins with large binding cavities and provides promising lead compounds for the development of TIPE2 inhibitors.