Covalent therapeutics has seen an increased interest since the late 90s with a noticeable surge in covalent inhibitor related patent applications and journal articles since 2014. Targeted covalent inhibitors (TCIs) offer the advantages of prologned duration of action, enhanced potency, lower dose and frequency in addition to reduced off-target events. There have been reports in that have also discussed increased patient compliance and effectiveness in drugging chemically intractable targets on occasion.
The CADD & chemoinformatics team at AIDD uses the virtual screening CovDock-VS, a Schrodinger software module, to provide several molecules as starting points that can serve as covalent inhibitors. The following generic protocol is typically followed in such a scenario.
Receptor reactive residue is mutated to Alanine
Consider the distance (< poses 5Å) to Cẞ atom of the reactive residue
Reconstruction of the Alanine back to its original amino acid, sampling of the residue rotamers
Select the ligand poses within 5Å and forming covalent bond according to the reaction specified
Minimization of the complex in gas-phase
Clustering of poses
Selection of the P-L complexes using glide-score
Ranking of the P-L complexes using glide-score
