On the quest of small molecules that can mimic Psalmotoxin-1, the most powerful peptidic modulator of the acid sensing channel ASIC1a.

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 a modulator. As a stimulus to improve this situation, this work was devised to assess the relative energies of binding cASIC1a to its most powerful modulator, the long peptide PcTx1. To this end, MD and QM-MM simulations in explicit water, based on crystal data for the PcTx1-cASIC1a complex, allowed disentangling the various interactions, assigning them a relative weight. Most relevant proved to be deeply buried salt bridges, generally also involving hydrogen bonds, formed by the guanidinium end chains of residues Arg26 and Arg27 on PcTx1 and carboxylate end chain of distant residues Asp and Glu on the acidic pocket of cASIC1a. In a preliminary attempt at exploiting these observations toward a small-molecule modulator, a ligand was modeled to interact with the two most important couples of residues, D238/D350 for R26 and E220/D408 for R27. Thus, a R26-R27 stretch, excised from the PcTx1-cASIC1a complex at low pH and modified by saturating all open valencies, on automated docking with ligand-free receptor was observed to establish salt bridges and hydrogen bonds with most of the above couples of residues. This strongly biased docking should pave the way to find small molecules that, by only exploiting a few points of interaction with the receptor, can mimic PcTx1. [ABSTRACT FROM AUTHOR]