A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE)

Abstract

Protein binding sites undergo ligand specific conformational changes upon ligand binding. However, most docking protocols rely on a fixed conformation of the receptor, or on the prior knowledge of multiple conformations representing the variation of the pocket, or on a known bounding box for the ligand. Here we described a general induced fit docking protocol that requires only one initial pocket conformation and identifies most of the correct ligand positions as the lowest score. We expanded a previously used diverse "cross-docking" benchmark to thirty ligand-protein pairs extracted from different crystal structures. The algorithm systematically scans pairs of neighbouring side chains, replaces them by alanines, and docks the ligand to each 'gapped' version of the pocket. All docked positions are scored, refined with original side chains and flexible backbone and re-scored. In the optimal version of the protocol pairs of residues were replaced by alanines and only one best scoring conformation was selected from each 'gapped' pocket for refinement. The optimal SCARE (SCan Alanines and REfine) protocol identifies a near native conformation (under 2Å RMSD) as the lowest rank for 80% of pairs if the docking bounding box is defined by the predicted pocket envelope, and for as many as 90% of the pairs if the bounding box is derived from the known answer with ~5 Å margin as used in most previous publications. The presented fully automated algorithm takes about two hours per pose of a single processor time, requires only one pocket structure and no prior knowledge about the binding site location. Furthermore, the results for conformationally conserved pockets do not deteriorate due to substantial increase of the pocket variability.

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

“…At least five different concentrations (spanning 3 orders of magnitude) were adjusted appropriately for the IC 50 of each compound examined. IC 50 values were computer-generated using a nonlinear regression formula (Graph-Pad, San Diego, CA) and were converted to K i values using the known K d values of the radioligands in the different tissues and using the Cheng−Prusoff equation. 42 K i values were means ± SEM of at least three determinations.…”

“…49 The simulation was performed according to the SCARE induced fit docking protocol that has been thoroughly described by Bottegoni and colleagues, 50 and it is only briefly summarized here. SCARE implements the flexibility of the receptor in the simulation generating different local versions of the binding pocket.…”

Protein Ligand Docking in Drug Discovery

“…Several residue rearrangements are grouped in sterically independent families and clusters of side-chain conformers are employed to achieve a good accuracy in the generated poses. The induced fit docking algorithm included in the SCARE (SCan Alanines and REfine) [63] protocol only requires one initial protein pocket conformation and identifies most of the correct ligand positions as the lowest score. It systematically scans pairs of neighbouring side chains, replaces them by alanine residues, and then docks the ligand to each 'gapped' pocket site.…”

“…Approaches addressing the protein flexibility can be classified as (i) MD and MC methods [4,94,120], (ii) simulated annealing, (iii) rotamer libraries [63,[121][122][123][124][125], (iv) protein ensemble grids [65,83,126], (v) soft-receptor modeling [112,[127][128][129], and (vi) collective degrees of freedom.…”

Protein Flexibility in Structure‐Based Virtual Screening: From Models to Algorithms

“…SCARE [76] systematically replaces pairs of neighboring residues by alanines intending to remove the area of the site that hinders the ligand to intrude. It thus generates an ensemble consisting of multiple gapped pocket versions.…”