Title:
FINDSITE LHM: A Threading-Based Approach to Ligand Homology Modeling
FINDSITE LHM: A Threading-Based Approach to Ligand Homology Modeling
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Author(s)
Brylinski, Michal
Skolnick, Jeffrey
Skolnick, Jeffrey
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Abstract
Ligand virtual screening is a widely used tool to assist in new pharmaceutical discovery. In practice, virtual screening
approaches have a number of limitations, and the development of new methodologies is required. Previously, we showed
that remotely related proteins identified by threading often share a common binding site occupied by chemically similar
ligands. Here, we demonstrate that across an evolutionarily related, but distant family of proteins, the ligands that bind to
the common binding site contain a set of strongly conserved anchor functional groups as well as a variable region that
accounts for their binding specificity. Furthermore, the sequence and structure conservation of residues contacting the
anchor functional groups is significantly higher than those contacting ligand variable regions. Exploiting these insights, we
developed FINDSITELHM that employs structural information extracted from weakly related proteins to perform rapid ligand
docking by homology modeling. In large scale benchmarking, using the predicted anchor-binding mode and the crystal
structure of the receptor, FINDSITELHM outperforms classical docking approaches with an average ligand RMSD from native
of ,2.5 A°
. For weakly homologous receptor protein models, using FINDSITELHM, the fraction of recovered binding residues
and specific contacts is 0.66 (0.55) and 0.49 (0.38) for highly confident (all) targets, respectively. Finally, in virtual screening
for HIV-1 protease inhibitors, using similarity to the ligand anchor region yields significantly improved enrichment factors.
Thus, the rather accurate, computationally inexpensive FINDSITELHM algorithm should be a useful approach to assist in the
discovery of novel biopharmaceuticals.
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Date Issued
2009-06-05
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