‘Vicarious’ structure-function information (mutagenesis, homology/isoform-based structural modeling, etc.) and
‘Wet’ structural biology (crystallography or NMR) yielding more ‘accurate’ modeling environment for the identification of pharmacophore models and ‘hot spots’
In addition, we did consider drug-/lead-like character of a ligand (MW, lipophilicity, cell permeability potential) including potential liabilities (RedOx, covalent bond formation, ‘active reactive’ species, etc).
A representative selection of targets analyzed and populated with focused small molecule ligands and their analogues is as follows:
HDACs class I-IV: the most studied family of epigenetic proteins to-date; importantly, we did include both pan- as well as ‘preferential’- (ex., class IIa) inhibitors; depending on your screening and ultimately therapeutic needs, these could be of utility
Notably, whereas there are several well characterized Class III HDAC (SirT) inhibitors, the respective direct activators are still lacking; in order to compensate for this ‘deficiency’, we included a subset of small molecules that were modeled into our internal model of SirT1 reflective of a multitude of pharmacological ideas including allosteric modulation
PRMTs (protein arginine methyltransferases), ex. CARM1, PRMT4, PRMT5; multiple series were modeled into the key protein-protein interaction PRMT5:MeP50 to yield a subset of compounds for this specific interface