{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:27:43Z","timestamp":1760236063332,"version":"build-2065373602"},"reference-count":103,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Regione Siciliana, Assessorship of Productive Activities\u2014Department of Productive Activities","award":["CUPG77B17000110001","CUPG29J18000700007"],"award-info":[{"award-number":["CUPG77B17000110001","CUPG29J18000700007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>In the last two decades, abnormal Ras (rat sarcoma protein)\u2013ERK (extracellular signal-regulated kinase) signalling in the brain has been involved in a variety of neuropsychiatric disorders, including drug addiction, certain forms of intellectual disability, and autism spectrum disorder. Modulation of membrane-receptor-mediated Ras activation has been proposed as a potential target mechanism to attenuate ERK signalling in the brain. Previously, we showed that a cell penetrating peptide, RB3, was able to inhibit downstream signalling by preventing RasGRF1 (Ras guanine nucleotide-releasing factor 1), a neuronal specific GDP\/GTP exchange factor, to bind Ras proteins, both in brain slices and in vivo, with an IC50 value in the micromolar range. The aim of this work was to mutate and improve this peptide through computer-aided techniques to increase its inhibitory activity against RasGRF1. The designed peptides were built based on the RB3 peptide structure corresponding to the \u03b1-helix of RasGRF1 responsible for Ras binding. For this purpose, the hydrogen-bond surrogate (HBS) approach was exploited to maintain the helical conformation of the designed peptides. Finally, residue scanning, MD simulations, and MM-GBSA calculations were used to identify 18 most promising \u03b1-helix-shaped peptides that will be assayed to check their potential activity against Ras-RasGRF1 and prevent downstream molecular events implicated in brain disorders.<\/jats:p>","DOI":"10.3390\/ph14111099","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T23:51:36Z","timestamp":1635465096000},"page":"1099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Rational Design of \u03b1-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5032-4888","authenticated-orcid":false,"given":"Maria Rita","family":"Gulotta","sequence":"first","affiliation":[{"name":"Molecular Informatics Unit, Fondazione Ri.MED, via Filippo Marini 14, 90128 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Brambilla","sequence":"additional","affiliation":[{"name":"Neuroscience and Mental Health Research Institute (NMHRI) and Neuroscience Division, School of Biosciences, Cardiff University, Haydn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2181-2468","authenticated-orcid":false,"given":"Ugo","family":"Perricone","sequence":"additional","affiliation":[{"name":"Molecular Informatics Unit, Fondazione Ri.MED, via Filippo Marini 14, 90128 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9728-3419","authenticated-orcid":false,"given":"Andrea","family":"Brancale","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1111\/ejn.12644","article-title":"Neural and psychological mechanisms underlying compulsive drug seeking habits and drug memories\u2014Indications for novel treatments of addiction","volume":"40","author":"Everitt","year":"2014","journal-title":"Eur. 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