Due to methodological advances and increased computer power, molecular dynamics (MD) based techniques have become feasible for application in drug design. MD simulations and Free Energy calculations can be used to investigate conformational variability of target proteins and to estimate ligand-receptor binding free energies.We will show examples how the results of such simulations can be used in lead identification and optimization of NCEs. In the NBE field, we use MD simulations to study the conformational dynamics of antibodies and nanobodies, in particular to assess the flexibility of CDRs. The trajectories, for instance, reveal the average solvent accessibility of residues that are prone to post-translational modification, e.g. oxidation of Methionine or deamidation of Asparagine. Insights obtained from these analyses influence sequence optimization considerations.Whether these techniques will become standard tools in drug discovery will depend not only on the accuracy of their results, but also on the availability of standardized and reliable setup and analysis procedures, as often human time rather than computing time turns out to be the bottleneck.

MD simulations in pharmaceutical research - examples and lessons learnt

243rd National Meeting (2012)

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