Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry
Abstract
:1. Introduction
2. Target Validation and Engagement
2.1. Chemical Biology Approaches to Reprogram the Transcriptome of Bacteria and Select Drug Candidates
2.2. Chemical Biology Strategies to Quantify Target Engagement
3. Chemical Biology Strategies to Identify New Hits
3.1. Screening of Focused Libraries or Clinical Compounds Libraries on Metalloproteases
3.2. Kinetic Target Guided Synthesis
3.3. Fragment-Based Drug Discovery
3.3.1. Discovery of Fragments Targeting EthR and EthR2
3.3.2. Discovery of Fragments as Inhibitors of MabA
4. Chemical Biology Approaches to ADME Properties Modulation
4.1. Controlling Target Engagement by Innovative Molecular Engineering
4.2. Rationalizing and Optimizing Plasma Stability
4.3. Controlling the Cell Clock In Vivo with an Antedrug to Understand a Clinical Observation
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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R | H | ||
Cpd | 3 | 24 | |
In vitro activity | |||
hTGR5 EC50 (nM) | 35 | 24 | |
mTGR5 EC50 (nM) | 0.8 | 0.4 | |
In vitro ADME properties | |||
Solubility (µM) a | 6.3 | >200 | |
LogD (7.4) b | 3.5 | 0.8 | |
Papp A-B c | 5.32 | 0.031 | |
Papp B-A c | 5.47 | 19 | |
Efflux ratio c | 1 | 636 | |
Clint d | 1287 | 1211 | |
In vivo PK properties e | |||
[C]plasmamax (nM) | NT | 102 | |
Fecal recovery (%) f | NT | 100 |
R | H | |||||
Cpd | 2 | P7 | P9 | P11 | P12 | |
n (PEG unit) | - | 4–13 | 11–25 | 31–57 | 100–138 | |
MW (g/mol) | 516 | 824–1220 | 1132–1748 | 2012–3156 | 5048–6720 | |
In vitro activity | ||||||
hTGR5 EC50 (nM) | 20 | 60 | 145 | 515 | 1102 | |
mTGR5 EC50 (nM) | 0.8 | 5 | 13 | 25 | 63 | |
In vitro ADME properties | ||||||
Solubility (µM) a | 8.8 | 151 | >200 | >200 | >2 00 | |
LogD7.4 | 3.97 | 3.42 | 1.58 | −1.53 | −1.58 | |
Clint b | 1254 | 524 | 17 | 8 | 11 | |
Papp A-B c | 9.3 | 4.9 | <0.02 | <0.12 | NT | |
Papp B-A c | 8.5 | 19.5 | 9.1 | <0.03 | NT |
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Deprez, B.; Bosc, D.; Charton, J.; Couturier, C.; Deprez-Poulain, R.; Flipo, M.; Leroux, F.; Villemagne, B.; Willand, N. Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry. Molecules 2021, 26, 6083. https://doi.org/10.3390/molecules26196083
Deprez B, Bosc D, Charton J, Couturier C, Deprez-Poulain R, Flipo M, Leroux F, Villemagne B, Willand N. Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry. Molecules. 2021; 26(19):6083. https://doi.org/10.3390/molecules26196083
Chicago/Turabian StyleDeprez, Benoit, Damien Bosc, Julie Charton, Cyril Couturier, Rebecca Deprez-Poulain, Marion Flipo, Florence Leroux, Baptiste Villemagne, and Nicolas Willand. 2021. "Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry" Molecules 26, no. 19: 6083. https://doi.org/10.3390/molecules26196083