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Cell Surface Transporters and Novel Drug Developments

Despite the numerous scientific and technological advances made within the last decade the attrition rates for new drug discovery remain as high as 95% for anticancer drugs. Recent drug development has been in part guided by Lipinski’s Rule of 5 (Ro5) even though many approved drugs do not comply to...

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Autores principales: Carmichael, Natasha, Day, Philip J. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8957865/
https://www.ncbi.nlm.nih.gov/pubmed/35350751
http://dx.doi.org/10.3389/fphar.2022.852938
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author Carmichael, Natasha
Day, Philip J. R.
author_facet Carmichael, Natasha
Day, Philip J. R.
author_sort Carmichael, Natasha
collection PubMed
description Despite the numerous scientific and technological advances made within the last decade the attrition rates for new drug discovery remain as high as 95% for anticancer drugs. Recent drug development has been in part guided by Lipinski’s Rule of 5 (Ro5) even though many approved drugs do not comply to these rules. With Covid-19 vaccine development strategy dramatically accelerating drug development perhaps it is timely to question the generic drug development process itself to find a more efficient, cost effective, and successful approach. It is widely believed that drugs permeate cells via two methods: phospholipid bilayer diffusion and carrier mediated transporters. However, emerging evidence suggests that carrier mediated transport may be the primary mechanism of drug uptake and not diffusion as long believed. Computational biology increasingly assists drug design to achieve desirable absorption, distribution, metabolism, elimination and toxicity (ADMET) properties. Perfecting drug entry into target cells as a prerequisite to intracellular drug action is a logical and compelling route and is expected to reduce drug attrition rates, particularly gaining favour amongst chronic lifelong therapeutics. Novel drug development is rapidly expanding from the utilisation of beyond the rule of five (bRo5) to pulsatile drug delivery systems and fragment based drug design. Utilising transporters as drug targets and advocating bRo5 molecules may be the solution to increasing drug specificity, reducing dosage and toxicity and thus revolutionising drug development. This review explores the development of cell surface transporter exploitation in drug development and the relationship with improved therapeutic index.
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spelling pubmed-89578652022-03-28 Cell Surface Transporters and Novel Drug Developments Carmichael, Natasha Day, Philip J. R. Front Pharmacol Pharmacology Despite the numerous scientific and technological advances made within the last decade the attrition rates for new drug discovery remain as high as 95% for anticancer drugs. Recent drug development has been in part guided by Lipinski’s Rule of 5 (Ro5) even though many approved drugs do not comply to these rules. With Covid-19 vaccine development strategy dramatically accelerating drug development perhaps it is timely to question the generic drug development process itself to find a more efficient, cost effective, and successful approach. It is widely believed that drugs permeate cells via two methods: phospholipid bilayer diffusion and carrier mediated transporters. However, emerging evidence suggests that carrier mediated transport may be the primary mechanism of drug uptake and not diffusion as long believed. Computational biology increasingly assists drug design to achieve desirable absorption, distribution, metabolism, elimination and toxicity (ADMET) properties. Perfecting drug entry into target cells as a prerequisite to intracellular drug action is a logical and compelling route and is expected to reduce drug attrition rates, particularly gaining favour amongst chronic lifelong therapeutics. Novel drug development is rapidly expanding from the utilisation of beyond the rule of five (bRo5) to pulsatile drug delivery systems and fragment based drug design. Utilising transporters as drug targets and advocating bRo5 molecules may be the solution to increasing drug specificity, reducing dosage and toxicity and thus revolutionising drug development. This review explores the development of cell surface transporter exploitation in drug development and the relationship with improved therapeutic index. Frontiers Media S.A. 2022-03-08 /pmc/articles/PMC8957865/ /pubmed/35350751 http://dx.doi.org/10.3389/fphar.2022.852938 Text en Copyright © 2022 Carmichael and Day. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Carmichael, Natasha
Day, Philip J. R.
Cell Surface Transporters and Novel Drug Developments
title Cell Surface Transporters and Novel Drug Developments
title_full Cell Surface Transporters and Novel Drug Developments
title_fullStr Cell Surface Transporters and Novel Drug Developments
title_full_unstemmed Cell Surface Transporters and Novel Drug Developments
title_short Cell Surface Transporters and Novel Drug Developments
title_sort cell surface transporters and novel drug developments
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8957865/
https://www.ncbi.nlm.nih.gov/pubmed/35350751
http://dx.doi.org/10.3389/fphar.2022.852938
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