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

Abstract

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.

Biological Activity of Natural and Synthetic Compounds

“…Modern computational approaches are often successfully used in the drug discovery process, as in the case of Stefanucci et al, who performed a virtual screening study on a large library of compounds, followed by lead optimization and molecular dynamics simulations, to identify tripeptides targeting kappa opioid receptor (KOR). The synthesized hit compounds displayed a good antinociceptive effect in vivo, thus supporting the reliability of the computational protocol [11]. Considering the widely reported biological activities of pyrrolo[1,2-a]quinoline derivatives, a novel series of synthetic compounds possessing this scaffold were screened in vitro on Candida albicans, and molecular modeling studies were performed against C. albicans pathogenic proteins.…”

Virtual Screening of Peptide Libraries: The Search for Peptide-Based Therapeutics Using Computational Tools

“…The critical role played by in silico tools for the discovery of novel bioactive peptides has been proved in different biomedical fields, such as the development of therapeutics against cancer or viral infections, immune system regulators, antidepressants, anxiolytics, analgesics, as well as peptides for the treatment of nicotine addiction, hypertension, Parkinson's disease, and neuropathic pains [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119].…”

“…As mentioned before, selecting a proper target is critical [105,106]. For instance, in silico protocols with the purpose of providing novel potential antidepressants, anxiolytics, and analgesics can be set up based on the kappa opioid receptor (KOR), the γ-Aminobutyric acid (GABA)-A receptors, and the α2δ auxiliary subunit of V-gated Ca 2+ channels (VGCCs) [105,106].…”

“…As mentioned before, selecting a proper target is critical [105,106]. For instance, in silico protocols with the purpose of providing novel potential antidepressants, anxiolytics, and analgesics can be set up based on the kappa opioid receptor (KOR), the γ-Aminobutyric acid (GABA)-A receptors, and the α2δ auxiliary subunit of V-gated Ca 2+ channels (VGCCs) [105,106]. A computational study was planned to identify compounds targeting KOR by including drug design, lead optimization, and molecular dynamics (MD) steps [105].…”

Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration

“…administration in the formalin-induced paw flinch test. 13 The novel tetrapeptides as C-terminal amides were obtained in good overall yields and high purity after RP-HPLC purification [for details see the Supporting Information (SI)]; 19 LRMS and 1 H NMR were applied for structural identification. 20 The final products as TFA salts were used for in vitro biological assays (Table 1).…”