Stalis : A Computational Method for Template‐Based Ab Initio Ligand Design

Proteins interact with small molecules through specific molecular recognition, which is central to essential biological functions in living systems. Therefore, understanding such interactions is crucial for basic sciences and drug discovery. Here, we present S tructure t emplate‐based a b initio li gand design s olution ( Stalis ), a knowledge‐based approach that uses structure templates from the Protein Data Bank libraries of whole ligands and their fragments and generates a set of molecules (virtual ligands) whose structures represent the pocket shape and chemical features of a given target binding site. Our benchmark performance evaluation shows that ligand structure‐based virtual screening using virtual ligands from Stalis outperforms a receptor structure‐based virtual screening using AutoDock Vina, demonstrating reliable overall screening performance applicable to computational high‐throughput screening. However, virtual ligands from Stalis are worse in recognizing active compounds at the small fraction of a rank‐ordered list of screened library compounds than crystal ligands, due to the low resolution of the virtual ligand structures. In conclusion, Stalis can facilitate drug discovery research by designing virtual ligands that can be used for fast ligand structure‐based virtual screening. Moreover, Stalis provides actual three‐dimensional ligand structures that likely bind to a target protein, enabling to gain structural insight into potential ligands. Stalis can be an efficient computational platform for high‐throughput ligand design for fundamental biological study and drug discovery research at the proteomic level. © 2019 Wiley Periodicals, Inc.