Computational Drug Design and Synthesis - Biophysical Chemistry - Computational Organic Chemistry

Medicinal chemistry: P2X7 receptor

The P2X7 receptor (P2X7R) for ATP is a therapeutic target for pathophysiological states including inflammation, pain management and epilepsy.The is a steady increase on interest for optimization of new P2X7 receptor antagonists from a growing list of pharmaceutical companies and academic groups (Guile et al. J. Med. Chem. 2009, 52, 3123). Drug library screening identified  N-[2-[[2-[(2-hydroxyethyl)amino]ethyl]amino]-5-quinolinyl]-2-tricyclo[3.3.1.13,7]dec-1-lacetamide dihydrochloride, known as AZ10606120. AZ10606120 is an adamantane derivative (Scheme 1) and a selective antagonist for P2X7Rs (IC50 of ca 10 nM).

Scheme 1. The structure of selective P2X7 antagonist AZ10606120.

The crystal structure of AZ10606120 with P2X7 (PDB ID 5U1W) revealed an allosteric binding pocket for the antagonist. The structure of the complex includes three antagonists per each receptor (Figure 1).

We are working on explaining the molecular basis of the binding and activity of analogs of  AZ10606120 on P2X7 ion channels and suggest compounds interesting to be synthesized (with Professor S. Vazquez, Organic Chemitry, Barcelona).

In more detail, molecular dynamics simulations and MM-GNSA free energy calculations are performed in order to explain structure-activity relationships and identify key residues for the interactions between compounds and P2X7.

Figure 1. (A) Top view and (B) side viewEach chain is represented by different color.