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Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies

Rheumatoid arthritis (RA) is a debilitating autoimmune disorder with an inflammatory condition targeting the joints that affects millions of patients worldwide. Several unmet needs still need to be addressed despite recent improvements in the management of RA. Although current RA therapies can dimin...

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Autores principales: Radu, Andrei-Flavius, Bungau, Simona Gabriela, Negru, Andrei Paul, Uivaraseanu, Bogdan, Bogdan, Mihaela Alexandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10300981/
https://www.ncbi.nlm.nih.gov/pubmed/37375255
http://dx.doi.org/10.3390/molecules28124699
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author Radu, Andrei-Flavius
Bungau, Simona Gabriela
Negru, Andrei Paul
Uivaraseanu, Bogdan
Bogdan, Mihaela Alexandra
author_facet Radu, Andrei-Flavius
Bungau, Simona Gabriela
Negru, Andrei Paul
Uivaraseanu, Bogdan
Bogdan, Mihaela Alexandra
author_sort Radu, Andrei-Flavius
collection PubMed
description Rheumatoid arthritis (RA) is a debilitating autoimmune disorder with an inflammatory condition targeting the joints that affects millions of patients worldwide. Several unmet needs still need to be addressed despite recent improvements in the management of RA. Although current RA therapies can diminish inflammation and alleviate symptoms, many patients remain unresponsive or experience flare-ups of their ailment. The present study aims to address these unmet needs through in silico research, with a focus on the identification of novel, potentially active molecules. Therefore, a molecular docking analysis has been conducted using AutoDockTools 1.5.7 on Janus kinase (JAK) inhibitors that are either approved for RA or in advanced phases of research. The binding affinities of these small molecules against JAK1, JAK2, and JAK3, which are target proteins implicated in the pathophysiology of RA, have been assessed. Subsequent to identifying the ligands with the highest affinity for these target proteins, a ligand-based virtual screening was performed utilizing SwissSimilarity, starting with the chemical structures of the previously identified small molecules. ZINC252492504 had the highest binding affinity (−9.0 kcal/mol) for JAK1, followed by ZINC72147089 (−8.6 kcal/mol) for JAK2, and ZINC72135158 (−8.6 kcal/mol) for JAK3. Using SwissADME, an in silico pharmacokinetic evaluation showed that oral administration of the three small molecules may be feasible. Based on the preliminary results of the present study, additional extensive research is required for the most promising candidates to be conducted so their efficacy and safety profiles can be thoroughly characterized, and they can become medium- and long-term pharmacotherapeutic solutions for the treatment of RA.
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spelling pubmed-103009812023-06-29 Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies Radu, Andrei-Flavius Bungau, Simona Gabriela Negru, Andrei Paul Uivaraseanu, Bogdan Bogdan, Mihaela Alexandra Molecules Article Rheumatoid arthritis (RA) is a debilitating autoimmune disorder with an inflammatory condition targeting the joints that affects millions of patients worldwide. Several unmet needs still need to be addressed despite recent improvements in the management of RA. Although current RA therapies can diminish inflammation and alleviate symptoms, many patients remain unresponsive or experience flare-ups of their ailment. The present study aims to address these unmet needs through in silico research, with a focus on the identification of novel, potentially active molecules. Therefore, a molecular docking analysis has been conducted using AutoDockTools 1.5.7 on Janus kinase (JAK) inhibitors that are either approved for RA or in advanced phases of research. The binding affinities of these small molecules against JAK1, JAK2, and JAK3, which are target proteins implicated in the pathophysiology of RA, have been assessed. Subsequent to identifying the ligands with the highest affinity for these target proteins, a ligand-based virtual screening was performed utilizing SwissSimilarity, starting with the chemical structures of the previously identified small molecules. ZINC252492504 had the highest binding affinity (−9.0 kcal/mol) for JAK1, followed by ZINC72147089 (−8.6 kcal/mol) for JAK2, and ZINC72135158 (−8.6 kcal/mol) for JAK3. Using SwissADME, an in silico pharmacokinetic evaluation showed that oral administration of the three small molecules may be feasible. Based on the preliminary results of the present study, additional extensive research is required for the most promising candidates to be conducted so their efficacy and safety profiles can be thoroughly characterized, and they can become medium- and long-term pharmacotherapeutic solutions for the treatment of RA. MDPI 2023-06-12 /pmc/articles/PMC10300981/ /pubmed/37375255 http://dx.doi.org/10.3390/molecules28124699 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Radu, Andrei-Flavius
Bungau, Simona Gabriela
Negru, Andrei Paul
Uivaraseanu, Bogdan
Bogdan, Mihaela Alexandra
Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies
title Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies
title_full Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies
title_fullStr Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies
title_full_unstemmed Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies
title_short Novel Potential Janus Kinase Inhibitors with Therapeutic Prospects in Rheumatoid Arthritis Addressed by In Silico Studies
title_sort novel potential janus kinase inhibitors with therapeutic prospects in rheumatoid arthritis addressed by in silico studies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10300981/
https://www.ncbi.nlm.nih.gov/pubmed/37375255
http://dx.doi.org/10.3390/molecules28124699
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