This is part of our series of industrial talks.

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Title: Characterising the unbound state of drug-like compounds: implications for molecular recognition

Speaker: Nicolas Foloppe (Vernalis)

Abstract:

The unbound state of drug compounds is important to better understand their binding to proteins, including conformational preorganization and the intramolecular reorganization energy of compounds upon binding (ΔEReorg). These questions were addressed with molecular dynamics (MD) simulations of diverse compounds, unbound or complexed to their protein target. Analysis of those systems involved observations regarding their electrostatics.

The unbound compounds simulated with MD were compared to conformers generated with implicit generalized Born (GB) aqueous solvation models. The notion of conformational pre-organization for binding was investigated by comparing the simulated compounds to their bioactive X-ray structure. The study yielded low to moderate values of ΔEReorg for most, but not all, compounds. For three particularly polar compounds, ΔEReorg was substantial (≥ 15 kcal/mol). Those large ΔEReorg values may be interpreted as a redistribution of electrostatic interactions upon binding.