- Poster presentation
- Open Access
The assessment of computationally derived protein ensembles in protein-ligand docking
Journal of Cheminformaticsvolume 4, Article number: P34 (2012)
The inclusion of receptor flexibility in protein-ligand docking experiments has become a major research interest in drug discovery [1, 2]. One of the possible methods applied is the use of multiple discrete protein conformations, so called ensemble docking [3, 4]. With computational techniques like Molecular Dynamics (MD) a large number of different conformations can be generated, not all of which can or should be included in the docking or virtual screening process . The question arises if and how suitable protein conformations can be selected systematically a priori based on quantifiable conformational features.
For neuraminidase and cyclin-dependent kinase II (CDK2), snapshots of MD simulation trajectories have been clustered based on different structural properties using a variety of clustering methods. To establish a possible correlation between docking performance and target conformational attributes the clustered snapshots have been subjected to extensive self- and cross-docking experiments as well as virtual screening using the GOLD docking programme. It is shown that conformationally similar snapshots do not necessarily result in a similar docking or virtual screening performance. The selection of the particular structural property on which to base the clustering appears to be the essential problem.
Carlson HA: Protein flexibility and drug design: how to hit a moving target. Curr Opin Chem Biol. 2002, 6: 447-452. 10.1016/S1367-5931(02)00341-1.
Durrant JD, McCammon JA: Computer-aided drug-discovery techniques that account for receptor flexibility. Curr Opin Pharmacol. 2010, 10: 770-774. 10.1016/j.coph.2010.09.001.
Barril X, Morley DS: Unveiling the full potential of flexible receptor docking using multiple crystallographic structures. J Med Chem. 2005, 48: 4432-4443. 10.1021/jm048972v.
Huang S-Y, Zou H: Ensemble docking of multiple protein structures: considering protein structural variations in molecular docking. Proteins. 2007, 66: 399-421.
Lin J-H, Perryman AL, Schames JR, McCammon JA: Computational drug design accomodating receptor flexibility: the relaxed complex scheme. J Am Chem Soc. 2002, 124: 5632-5633. 10.1021/ja0260162.