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Rigid body docking for Virtual Screening

Please always quote using this URN: urn:nbn:de:0297-zib-7690
  • A recently developed algorithm allows Rigid Body Docking of ligands to proteins, regardless of the accessibility and location of the binding site. The Docking procedure is divided into three subsequent optimization phases, two of which utilize rigid body dynamics. The last one is applied with the ligand already positioned inside the binding pocket and accounts for full flexibility. Initially, a combination of geometrical and force-field based methods is used as a Coarse Docking strategy, considering only Lennard-Jones interactions between the target and pharmaceutically relevant atoms or functional groups. The protein is subjected to a Hot Spot Analysis, which reveals points of high affinity in the protein environment towards these groups. The hot spots are distributed into different subsets according to their group affiliation. The ligand is described as a complementary point set, consisting of the same subsets. Both sets are matched in $\mathrm{I\!R}^{3}$, by superimposing members of the same subsets. In the first instance, steric inhibition is nearly neglected, preventing the system's trajectory from trapping in local minima and thus from finding false positive solutions. Hence the exact location of the binding site can be determined fast and reliably without any additional information. Subsequently, errors resulting from approximations are minimized via finetuning, this time considering both Lennard-Jones and Coulomb forces. Finally, the potential energy of the whole complex is minimized. In a first evaluation, results are rated by a reduced scoring function considering only noncovalent interaction energies. Exemplary Screening results will be given for specific ligands.

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Metadaten
Author:Andreas May, Steffen Eisenhardt, Johannes Schmidt-Ehrenberg, Frank Cordes
Document Type:ZIB-Report
Tag:docking; identification of active sites; point matching
MSC-Classification:62-XX STATISTICS / 62Pxx Applications [See also 90-XX, 91-XX, 92-XX] / 62P10 Applications to biology and medical sciences
92-XX BIOLOGY AND OTHER NATURAL SCIENCES / 92Cxx Physiological, cellular and medical topics / 92C40 Biochemistry, molecular biology
Date of first Publication:2003/12/19
Series (Serial Number):ZIB-Report (03-47)
ZIB-Reportnumber:03-47
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