Surflex-Dock 2.1: Robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search

Abstract

The Surflex flexible molecular docking method has been generalized and extended in two primary areas related to the search component of docking. First, incorporation of a small-molecule force-field extends the search into Cartesian coordinates constrained by internal ligand energetics. Whereas previous versions searched only the alignment and acyclic torsional space of the ligand, the new approach supports dynamic ring flexibility and allatom optimization of docked ligand poses. Second, knowledge of well established molecular interactions between ligand fragments and a target protein can be directly exploited to guide the search process. This offers advantages in some cases over the search strategy where ligand alignment is guided solely by a ''protomol'' (a pre-computed molecular representation of an idealized ligand). Results are presented on both docking accuracy and screening utility using multiple publicly available benchmark data sets that place Surflex's performance in the context of other molecular docking methods. In terms of docking accuracy, Surflex-Dock 2.1 performs as well as the best available methods. In the area of screening utility, Surflex's performance is extremely robust, and it is clearly superior to other methods within the set of cases for which comparative data are available, with roughly double the screening enrichment performance.

Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor

“…The ligand-protein interaction energy was first evaluated using the energy scoring functions of the two docking programs GOLD (23) and Surflex (24,25). The scoring functions of these two programs lend themselves well to the current protein-ligand system given that the nature of the ligand-binding pocket is mostly hydrophobic with a few hydrogen bonding sites.…”

In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes

“…Molecular docking studies were carried out to understand the binding mode of the synthesized adamantyl derivatives 1-26 inside each of the cholinesterase enzymes using the Surflex-Dock package of Sybyl7.3 [25][26][27] software. Surflex is a fully automatic, flexible molecular docking algorithm that combines the scoring function from the Hammerhead docking system with a search engine that relies on a surface-based molecular similarity method as a means to rapidly generate suitable putative poses for molecular fragments.…”

Structure-based design of inhibitors of CXCR4.

“…In unpublished research, benchmarking Surflex-Dock [234,244] with three other common molecular docking programs, MolDock [245], DOCK [226], and Autodock [227], we found that Surflex-Dock consistently reproduced predicted compound binding modes as illustrated by compound/receptor crystal structures to a greater degree than the other docking programs. The SurflexDock [234,244] method is centered on development of a protomol, a pseudomolecule used to virtually define the binding site targeted on the protein structure. This proto mol can be generated based on available ligands, inhibitors or partner proteins or development can be designed based on a defined series of target residues composing an active site.…”

“…Our prior experience with the Surflex-Dock [234,244] docking program has demonstrated that this program is highly amenable to high-throughput virtual screening. In unpublished research, benchmarking Surflex-Dock [234,244] with three other common molecular docking programs, MolDock [245], DOCK [226], and Autodock [227], we found that Surflex-Dock consistently reproduced predicted compound binding modes as illustrated by compound/receptor crystal structures to a greater degree than the other docking programs.…”

“…The highest scoring conformations of the ECl VS compounds were utilized as a guide to initial placement of the inhibitor. As the initial virtual screens for the active compounds were targeted at the N 119S conformation of CXCR4 and the interface surface of Gai , the compounds were re-docked into the native structure using Surflex-Dock [234,244] . A novel protomol was generated for the native CXCR4 structure using the residues identified in Table 5, which adequately provided docking coverage to the Nterminus and extracellular loops two and three.…”