Screening a peptidyl database for potential ligands to proteins with side-chain flexibility

Abstract

The three key challenges addressed in our development of SPECITOPE, a tool for screening large structural databases for potential ligands to a protein, are to eliminate infeasible candidates early in the search, incorporate ligand and protein side-chain flexibility upon docking, and provide an appropriate rank for potential new ligands. The protein ligand-binding site is modeled by a shell of surface atoms and by hydrogen-bonding template points for the ligand to match, conferring specificity to the interaction. SPECITOPE combinatorially matches all hydrogen-bond donors and acceptors of the screened molecules to the template points. By eliminating molecules that cannot match distance or hydrogen-bond constraints, the transformation of potential docking candidates into the ligand-binding site and the shape and hydrophobic complementarity evaluations are only required for a small subset of the database. SPECITOPE screens 140,000 peptide fragments in about an hour and has identified and docked known inhibitors and potential new ligands to the free structures of four distinct targets: a serine protease, a DNA repair enzyme, an aspartic proteinase, and a glycosyltransferase. For all four, protein side-chain rotations were critical for successful docking, emphasizing the importance of inducible complementarity for accurately modeling ligand interactions. SPECITOPE has a range of potential applications for understanding and engineering protein recognition, from inhibitor and linker design to protein docking and macromolecular assembly.

Understanding the challenges of protein flexibility in drug design

“…In some methods, the ligand's pose is optimized before varying the protein side-chains [49], while in more recent methods, both the ligand and side-chain conformations are explored simultaneously [50], [51]. The latter methods have demonstrated significant improvement over rigid-protein docking [52], [53].…”

Improving database enrichment through ensemble docking

“…It was shown that the methods described in that protocol are very useful in predicting correct poses of bound ligands by accounting for induced fit effecting such as small movements in the backbone and significant changes in side-chain conformations of protein residues. Other groups have also developed protocols for accounting for protein flexibility in docking [10][11][12][13][14]. However, modeling large-scale changes in backbone conformations of proteins, including large loop movements, present significant challenges and therefore may require alternative methods.…”

Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B

“…[13][14][15][16][17][18][19][20] Nevertheless, molecular docking has some practical advantages. Although it has only a modest ability to distinguish between two compounds that both fit in an active site, it can reliably screen out compounds that do not fit in a binding site or that have grossly wrong electrostatic properties.…”