Abstract
A very simple, fast, and efficient scheme is proposed for performing preliminary protein–ligand docking as the first step of intensive high-throughput virtual screening. The procedure acts as a surface-complementarity filter that first calculates the 2D-contour maps of both the protein cavity and of the ligands using a spherical harmonics description of the associated molecular surfaces. Next, the obtained 2D-fingerprint images are compared to detect their complementarity. This scheme was tested on three typical cases of protein cavities, namely, a well-closed pocket, a small open pocket, and a large open one. For that purpose, for each case, a sample of 101 ligand conformers was generated (the X-ray one and 100 different conformers generated using simulated annealing), and these conformational samples were ranked according to the complementarity with the protein cavity surface. Compared to traditional docking procedures such as FRED (considered as typical of a very fast rigid body docking algorithms) and GOLD (considered as typical of the more accurate flexible docking algorithms), our procedure was much faster and more successful in detecting the right X-ray conformation. We did, however, identify a certain weakness in the case of the very large pocket where results were not as expected. In general, our method could be used for incorporating indirectly flexibility in protein–ligand docking calculations as such a scheme can easily handle several conformational states of both the protein and the ligand.
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Acknowledgements
This work was supported by the PRA B02-04 of the French–Chinese Association for Scientific and Technical Research (AFCRST), FAPESP 01/08895-0, FINEP 1945/01, and CNPq 401695/2003-4. BM was recipient of a CAPES visiting researcher fellowship while this work was performed. We thanks the CINES computer center in Montpellier for providing access to the GOLD program on their O3800 SGI machine, and OPENEYE for providing free access to all their software according to an academic license.
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MB proposed the fingerprint-matching algorithm, carried out the fingerprint-matching experiments and helped to draft the manuscript. NM carried out the docking experiments with FRED and GOLD. GN participated in the coordination and helped to draft the manuscript. WC generated the fingerprints using MSSH. XS generated the fingerprints using MSSH. BM participated in the design of the study, coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
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Yamagishi, M.E.B., Martins, N.F., Neshich, G. et al. A fast surface-matching procedure for protein–ligand docking. J Mol Model 12, 965–972 (2006). https://doi.org/10.1007/s00894-006-0109-z
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DOI: https://doi.org/10.1007/s00894-006-0109-z