Quantum mechanical studies of indirubin derived CDK and GSK3b inhibitors

Indirubins are natural products isolated from Gastropod mollusks and have been used for over 2500 years to produce the Tyrian purple dye among other applications. Indirubin molecular scaffold proved to be an ideal lead for inhibition of protein kinases[1–3]. More specifically, molecules like indirubin 3'oxime and 6BIO (6Br-indirubin 3'oxime, a commercial product) are highly potent and selective inhibitors of the Cyclin Dependent Kinases (CDKs) and Glycogen Synthase Kinase-3beta (GSK3β) respectively, receptors that are widely recognized as targets for several diseases including cancer. In order to elucidate structural features of the molecular geometry and electronic distribution that have impact on the binding affinity of the molecules, ab-initio quantum mechanic calculations have been performed to a series of 48 synthetic indirubins at the HF/6–31G** but also at the DFT/B3LYP 6–31G** level of theory post processed with Bader's quantum topological AIM theory. Critical features not easily inspectable by crystallography or simple spectral methods like bond lengths, planarity, and intramolecular hydrogen bonds were examined and special attention was paid to the pharmacophore of the indirubin scaffold. Calculations were interpreted on the basis of experimental results, IC₅₀ values and crystallographic structures of indirubin-kinase complexes and could assist further improvement of both potency and selectivity of naturally occurring indirubins

References: 1. Polychronopoulos, P. et al. (2004)J Med Chem 47:935–946

2. Myrianhopoulos, V. et al (2007)J Med Chem 50:4027–4037

3. Meijer, L. et al. (2003) Chem Biol 10: 1255–1266