The incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery
By M. Fischer, Ryan G. Coleman, James S. Fraser, Brian K. Shoichet. 2014
139 citations recorded by the source corpus.
Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here, we describe a flexible-docking method that samples and weights protein conformations using experimentally-derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in Cytochrome c Peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank where similar experimental information is available.
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
- Weili Nie
- Arash Vahdat
- Anima Anandkumar
- Zhuoran Qiao
- Thomas F. Miller
- Kamyar Azizzadenesheli
- Rong Ge
- Yuanzhi Li
Citations in the corpus
- Dynamic-Backbone Protein-Ligand Structure Prediction with Multiscale Generative Diffusion Models (2022, background): “While several schemes have been proposed to remedy these issues [11–20], such methods often require case-specific expert interventions and lack a unified framework to predict 3D structures in a systematic and cooperative fashion.”