It is 2012 but many of the inherent problems of in-silico drug discovery methods have not been resolved yet, such as; accuracte prediction of binding affinities, receptor flexibility, free energy calculation, realistic scoring functions, etc, to name a few. So these could be considered, as of today, as the main challenges of drug discovery methods, which should be solved in the forthcoming years.
Nevertheless, let's suppose that those questions have been more or less solved or improved. In such a hypothetical situation, what do you think would be the next challenging questions in drug discovery (mostly related with in silico methods)?
Really interesting answer. Now I am trying to find top related papers.