On the Quest of Small Molecules that Can Mimic Psalmotoxin-1, a Powerful Peptidic Modulator of the Acid Sensing Channel ASIC1a

Abstract

Acid-sensing ion channels (ASICs) are thought to play a key role in a number of pathologies, from neuronal injury to pain sensation, while no drug has yet been approved as their modulator. This work was devised to asses roughly, yet from first principles, the relative energies of binding in the most important acidic pocket of cASIC1a, thereby paving the way to find small molecules that can mimic Pctx1, the most powerful peptidic modulator of cASIC1a. To this end, MD simulations for the overall conformation, and QM-MM simulations specifically for the location of hydrogen atoms, allowed disentangling the relative weight of the various non-bonded interactions between PcTx1 and cASIC1a. Main weight could be attributed to deeply buried salt bridges formed by the guanidinium end chains of residues Arg26 and Arg27 on PcTx1 and carboxylate end chain of distant residues Asp and Glu on cASIC1a. Rewardingly, in a preliminary attempt at exploiting these observations toward a small-molecule modulator, a Arg26-Arg27 stretch, excised from the PcTx1-cASIC1a complex and slightly simplified, on automated rigid docking on ligand-free receptor was observed to form most of the above salt bridges.