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      Flexible ligand docking to multiple receptor conformations: a practical alternative

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      Current Opinion in Structural Biology

      Elsevier BV

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          Abstract

          State of the art docking algorithms predict an incorrect binding pose for about 50-70% of all ligands when only a single fixed receptor conformation is considered. In many more cases, lack of receptor flexibility results in meaningless ligand binding scores, even when the correct pose is obtained. Incorporating conformational rearrangements of the receptor binding pocket into predictions of both ligand binding pose and binding score is crucial for improving structure-based drug design and virtual ligand screening methodologies. However, direct modeling of protein binding site flexibility remains challenging because of the large conformational space that must be sampled, and difficulties remain in constructing a suitably accurate energy function. Here we show that using multiple fixed receptor conformations, either experimentally determined by crystallography or NMR, or computationally generated, is a practical shortcut that may improve docking calculations. In several cases, such an approach has led to experimentally validated predictions.

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          Author and article information

          Journal
          Current Opinion in Structural Biology
          Current Opinion in Structural Biology
          Elsevier BV
          0959440X
          April 2008
          April 2008
          : 18
          : 2
          : 178-184
          Article
          10.1016/j.sbi.2008.01.004
          2396190
          18302984
          © 2008

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