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The rise of molecular simulations in fragment-based drug design (FBDD): an overview

Fragment-based drug discovery (FBDD) is an innovative approach, progressively more applied in the academic and industrial context, to enhance hit identification for previously considered undruggable biological targets. In particular, FBDD discovers low-molecular-weight (LMW) ligands (<300 Da) abl...

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Detalles Bibliográficos
Autores principales: Bissaro, Maicol, Sturlese, Mattia, Moro, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Author(s). Published by Elsevier Ltd. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314695/
https://www.ncbi.nlm.nih.gov/pubmed/32592867
http://dx.doi.org/10.1016/j.drudis.2020.06.023
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author Bissaro, Maicol
Sturlese, Mattia
Moro, Stefano
author_facet Bissaro, Maicol
Sturlese, Mattia
Moro, Stefano
author_sort Bissaro, Maicol
collection PubMed
description Fragment-based drug discovery (FBDD) is an innovative approach, progressively more applied in the academic and industrial context, to enhance hit identification for previously considered undruggable biological targets. In particular, FBDD discovers low-molecular-weight (LMW) ligands (<300 Da) able to bind to therapeutically relevant macromolecules in an affinity range from the micromolar (μM) to millimolar (mM). X-ray crystallography (XRC) and nuclear magnetic resonance (NMR) spectroscopy are commonly the methods of choice to obtain 3D information about the bound ligand–protein complex, but this can occasionally be problematic, mainly for early, low-affinity fragments. The recent development of computational fragment-based approaches provides a further strategy for improving the identification of fragment hits. In this review, we summarize the state of the art of molecular dynamics simulations approaches used in FBDD, and discuss limitations and future perspectives for these approaches.
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spelling pubmed-73146952020-06-25 The rise of molecular simulations in fragment-based drug design (FBDD): an overview Bissaro, Maicol Sturlese, Mattia Moro, Stefano Drug Discov Today Review Fragment-based drug discovery (FBDD) is an innovative approach, progressively more applied in the academic and industrial context, to enhance hit identification for previously considered undruggable biological targets. In particular, FBDD discovers low-molecular-weight (LMW) ligands (<300 Da) able to bind to therapeutically relevant macromolecules in an affinity range from the micromolar (μM) to millimolar (mM). X-ray crystallography (XRC) and nuclear magnetic resonance (NMR) spectroscopy are commonly the methods of choice to obtain 3D information about the bound ligand–protein complex, but this can occasionally be problematic, mainly for early, low-affinity fragments. The recent development of computational fragment-based approaches provides a further strategy for improving the identification of fragment hits. In this review, we summarize the state of the art of molecular dynamics simulations approaches used in FBDD, and discuss limitations and future perspectives for these approaches. The Author(s). Published by Elsevier Ltd. 2020-09 2020-06-25 /pmc/articles/PMC7314695/ /pubmed/32592867 http://dx.doi.org/10.1016/j.drudis.2020.06.023 Text en © 2020 The Author(s) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Review
Bissaro, Maicol
Sturlese, Mattia
Moro, Stefano
The rise of molecular simulations in fragment-based drug design (FBDD): an overview
title The rise of molecular simulations in fragment-based drug design (FBDD): an overview
title_full The rise of molecular simulations in fragment-based drug design (FBDD): an overview
title_fullStr The rise of molecular simulations in fragment-based drug design (FBDD): an overview
title_full_unstemmed The rise of molecular simulations in fragment-based drug design (FBDD): an overview
title_short The rise of molecular simulations in fragment-based drug design (FBDD): an overview
title_sort rise of molecular simulations in fragment-based drug design (fbdd): an overview
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314695/
https://www.ncbi.nlm.nih.gov/pubmed/32592867
http://dx.doi.org/10.1016/j.drudis.2020.06.023
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