Automatic identification and representation of protein binding sites for molecular docking

Abstract

Molecular docking is a popular way to screen for novel drug compounds. The method involves aligning small molecules to a protein structure and estimating their binding affinity. To do this rapidly for tens of thousands of molecules requires an effective representation of the binding region of the target protein. This paper presents an algorithm for representing a protein's binding site in a way that is specifically suited to molecular docking applications. Initially, the protein's surface is coated with a collection of molecular fragments that could potentially interact with the protein. Each fragment, or probe, serves as a potential alignment point for atoms in a ligand, and is scored to represent that probe's affinity for the protein. Probes are then clustered by accumulating their affinities, where high affinity clusters are identified as being the "stickiest" portions of the protein surface. The stickiest cluster is used as a computational binding "pocket" for docking. This method of site identification was tested on a number of ligand-protein complexes; in each case the pocket constructed by the algorithm coincided with the known ligand binding site. Successful docking experiments demonstrated the effectiveness of the probe representation.

Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening

“…Surflex (Tripos, St. Louis, MO) is similar to FlexX in that a molecule is first fragmented, and the conformations of each piece are further explored. Here, a "protomol," an idealized active site ligand comprising a cluster of molecular fragments featuring the binding pocket surface (Ruppert et al, 1997), is generated and serves as a target for alignment of fragment conformations based on the molecular similarity method (Jain, 2003). An entire molecule is then assembled by the incremental construction approach (Welch et al, 1996) or a genetic algorithm called the "Whole Molecule Algorithm" (Jones et al, 1997).…”

Magnolol Inhibits LPS-induced NF-κB/Rel Activation by Blocking p38 Kinase in Murine Macrophages

“…We also showed that magnolol binds to the p38 kinase. The p38 kinase is an important mediator of stress-induced gene expression [21]. In particular, the p38 kinase is known to play a key role in LPS-induced signal transduction pathways leading to cytokine synthesis [15].…”

“…The molecule was fully minimized with GasteigerHückel charges. Docking study was performed using Surflex-Dock module of SYBYL 8.1, which uses empirical scoring function using protomol [21].…”

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

“…The ProtoMol is not meant to be an absolute docking envelope but its purpose is to direct the initial placement of the ligand during the docking process. Docked ligands are scored in the context of the receptor, not in the context of the ProtoMol [45]. To evaluate this docking technique with the C-BS, we used Surflex-Dock to dock selected inhibitors, namely T138067, ABT-751, colchicine and TN-16, as extracted from their X-ray structure in complex with the C-BS (protein data bank (PDB): 3HKE [46] for T138067, 3HKC [46] for ABT-751, 1SA0 [47] for colchicine and 3HKD [46] for TN-16) into the corresponding receptor binding site in silico (Figure 2).…”