What is the energy price paid by the ligand to adopt the bioactive conformation? What payoff can we expect by conformationally constraining a flexible ligand (or conversely, what does it cost us if we don’t)? These are common and important ligand design questions that drive lead optimization decisions. Historically, modelers try to answer this with the relative energy (hopefully solvation-corrected) of the ligand’s bioactive conformation compared to the global energy minimum, or with guesswork, or a mixture of the two. FreeForm allows us to calculate the overall free-ligand, free energy of the bioactive conformation, explicitly accounting for ligand flexibility, offering substantially improved answers to the key questions above.
In this webinar we will cover:
Conformer free energies within the unbound ligand ensemble.
How strain energy and ligand entropy relate to conformer free energy.
How not to calculate ligand entropy.
Constraining the ligand: can we know if it will help?