Abstract
The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are no significant matches, the ligand cannot be docked in the protein. Otherwise, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. This provides the docked ligand in the target enzyme. Previously, CLASP was used to predict and validate (in vivo) the inhibition of phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus by two dipeptidyl peptidase-IV (DPP4) inhibitors - vildagliptin and K-579. In the current work, vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. The docked ligand is free from steric clashes and interacts with the same side chain residues that bind myo-inositol, providing corroboration of the validity of the proposed methodology.
Highlights
The ability to computationally predict protein-ligand interactions with accuracy is an invaluable asset, since it allows for large scale screening at minimal costs[1,2]
Protein docking methods are a subset of these methods, characterized by their ability to score a large number of possible conformations using fast algorithms
DOCLASP takes as input a set of proteins with known structures which bind a particular ligand, and a target protein into which the ligand is to be docked. Each of these holo structures is used to define a motif consisting of the first four residues making non-hydrophobic interactions. These motifs are used to query the target protein, using an enhanced version of the search engine used by CLASP that uses precompiled databases[16], and significant congruent matches are identified
Summary
The ability to computationally predict protein-ligand interactions with accuracy is an invaluable asset, since it allows for large scale screening at minimal costs[1,2]. Each of these holo structures is used to define a motif consisting of the first four residues making non-hydrophobic interactions These motifs are used to query the target protein, using an enhanced version of the search engine used by CLASP that uses precompiled databases[16], and significant congruent matches are identified. These significant matches in the target protein are superimposed to the binding residues (the motif) in the corresponding holoenzyme(s), creating a unified coordinate framework formed by the holoenzyme, the ligand and the target enzyme. The current work presents a fast methodology for docking ligands into protein structures based on spatial and electrostatic congruence of known binding sites to putative binding targets
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