Calcium Ion Channel Targeted Library
A set of calcium ion channel modulators designed using various ligand-based approaches
4 550 compounds
Calcium ion channels are responsible for surprisingly large variety of physiological functions. Intracellular calcium ions serve as a second messenger of electrical signaling, initiating many different cellular events. Although design of calcium channel blockers is challenging due to heterogeneity of these biological targets and hence need for design of selective antagonists for different channel subtypes, they offer great opportunities since their validation is provided by numerous marketed drugs.
Enamine voltage-gated targeted library encompasses both known chemotypes and molecules based on novel scaffolds identified in our in silico studies and MedChem-based scaffold hopping projects.
We have undertaken in-depth analysis of known calcium channel blockers and carefully selected most promising drug-like structures from our screening collection exceeding 2 633 614 small-molecular-weight compounds.
- Privileged chemotypes such as dihydropyridines, GABA analogues, succinimides, 4-substituted prolines, and quinazolines were included in the library.
- Pharmacophore modelling was carried out for several relevant calcium channel blockers resulting in about 1 700 compound set.
- Scaffold hopping was used. In particular, it is known that many known calcium channel blockers contain piperazine or 4-aminopiperidine moiety. Recently, several successful examples of bioisosteric replacements of these motifs by other diamine cores have been reported. We have extended this approach to a rich variety of unique analogues of piperazine and 4-aminopiperidine available exclusively from Enamine, as well as other cores, e.g. imidazopyridazines, which resulted in a set of completely novel compounds.
- Only drug-like compounds with the most attractive structural and physico-chemical properties were included (HDon 0...4, HAcc: 1...8, RotBonds: 0...10, TPSA 3...140 Å2, average Fsp3 0.38). This resulted in 100% Ro5-compliant library, with 86% of the compounds being lead-like.