In Silico Identification of Tripeptides as Lead Compounds for the Design of KOR Ligands.

Stefanucci, Azzurra; Iobbi, Valeria; Della Valle, Alice; Scioli, Giuseppe; Pieretti, Stefano; Minosi, Paola; Mirzaie, Sako; Novellino, Ettore; Mollica, Adriano

The kappa opioid receptor (KOR) represents an attractive target for the development of drugs as potential antidepressants, anxiolytics and analgesics. A robust computational approach may guarantee a reduction in costs in the initial stages of drug discovery, novelty and accurate results. In this work, a virtual screening workflow of a library consisting of ~6 million molecules was set up, with the aim to find potential lead compounds that could manifest activity on the KOR. This in silico study provides a significant contribution in the identification of compounds capable of interacting with a specific molecular target. The main computational techniques adopted in this experimental work include: (i) virtual screening; (ii) drug design and leads optimization; (iii) molecular dynamics. The best hits are tripeptides prepared via solution phase peptide synthesis. These were tested in vivo, revealing a good antinociceptive effect after subcutaneous administration. However, further work is due to delineate their full pharmacological profile, in order to verify the features predicted by the in silico outcomes.

TRIPEPTIDES; DRUG target; DRUG design; MOLECULAR dynamics; KETAMINE

Molecules, 2021, Vol 26, Issue 16, p4767

1420-3049

Academic Journal

10.3390/molecules26164767