Fast Structure-Based Virtual Ligand Screening Combining FRED, DOCK, and Surflex

Abstract

A protocol was devised in which FRED, DOCK, and Surflex were combined in a multistep virtual ligand screening (VLS) procedure to screen the pocket of four different proteins. One goal was to evaluate the impact of chaining "freely available packages to academic users" on docking/scoring accuracy and CPU time consumption. A bank of 65 660 compounds including 49 known actives was generated. Our procedure is successful because docking/scoring parameters are tuned according to the nature of the binding pocket and because a shape-based filtering tool is applied prior to flexible docking. The obtained enrichment factors are in line with those reported in recent studies. We suggest that consensus docking/scoring could be valuable to some drug discovery projects. The present protocol could process the entire bank for one receptor in less than a week on one processor, suggesting that VLS experiments could be performed even without large computer resources.

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

“…The latter measures the ability of a docking algorithm, given a single protein structure, to correctly rank a set of known active ligands against a background of putative inactives (called decoys). A recent and valuable trend within the field has been the use of standard benchmarks on multiple methods [16][17][18][19][20][21][22]. For the work reported here, benchmarks were selected either for which previous versions of Surflex-Dock had been tested [16,17,19] in order to show the effects of new features, or where protein and ligand structures were publicly available along with performance of widely used methods [23,24].…”

Design of protein–membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V

“…We used an efficient multistep procedure that is both time-and cost-effective (16,33) and studied the 500,000-molecule ChemBridge compound collection. Absorption, distribution, metabolism, and excretion/tox filtering was performed with Filter (OpenEye Scientific Software, Santa Fe, NM) and FAF-Drugs (41).…”

“…However, these computational approaches also suffer from limitations (9). We applied our validated multistep SB-VLS protocol (16,33) to both the open and closed C2 crystal forms and selected the best 509 molecules for each receptor form (i.e., we decided to screen Ϸ1,000 compounds in total). These 1,018 molecules were tested in groups of four compounds (each at a final concentration of 100 M) for their ability to inhibit prothrombin activation.…”

“…In the present study, we initially ignored the data on FVIII, to evaluate the strengths and weaknesses of SB-VLS approaches. The advantages of using hierarchical SB-VLS protocols with rigid body docking before flexible ligand docking is that the computations run significantly faster (thus can be carried out on only one workstation in Ϸ2 weeks) than full flexible ligand docking of the entire compound collection (Ϸ8 weeks on the same single workstation) while performing better or equally well (10,16,33). The hierarchical approach used here is also very interesting when several 3D structures of the receptor are available, because again, the computations can be performed on a few workstations in parallel.…”

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.…”