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Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates
Open accessAbstract
The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compounds with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clinical candidates with molecular weight (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramolecular hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets.
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“In the development of new drugs, 500 Da is often quoted as the maximum molecular weight parameter. However, it has been observed that molecules with higher molecular weights are also capable of being absorbed, and the limits of oral bioavailability appear to extend to about MW ≤ 1000 Da [70,71,72].”
From The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science (2023) · cites this paper as [71]
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“In general, PROTAC physicochemical property space falls beyond the ‘rule of 5’ (refs59,60) owing to the bifunctional nature of the molecules.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [60]
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Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis
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“Therefore, opti izing the physiochemical properties of drug candidates to evade these processes has become an integral part of the drug discovery paradigm [25,40,41].”
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Cyclosporin Structure and Permeability: From A to Z and Beyond
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Self-citationChallenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis
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“Despite these facts, a close analysis of the currently marketed drugs used for the treatment of several diseases, that must be by definition harmless and effective, shows that a small percentage of them present a panoply of “forbidden” functionalities (structural alerts) and “unacceptable” properties, including endope…”
BackgroundMolecular chameleons in drug discovery
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Metadata
- Authors
- Doak, B. C., Over, B., Giordanetto, F., & Kihlberg, J.
- Affiliations
- Uppsala University (SE)
- Corresponding author
- Kihlberg, Jan
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 21
- Issue
- 9
- Pages
- 1115-1142
- ISSN
- 1074-5521 (ISSN-L)
- OpenAlex
- W2106605095
- Cited by
- 835
- References
- 295
- Citations by year
- 2026: 101 · 2025: 82 · 2024: 103 · 2023: 111 · 2022: 103 · 2021: 88 · 2020: 65 · 2019: 50 · 2018: 51 · 2017: 27 · 2016: 37 · 2015: 14
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Uppsala Universitet
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- Rule of 5, oral bioavailability, drug discovery, molecular weight, intramolecular hydrogen bonding, macrocyclization, oral dosage forms, natural products, structure-based drug design, pharmacokinetics, clinical candidates
- MeSH terms
- Administration, Oral, Biological Products, Pharmaceutical Preparations, Humans, Molecular Weight, Protease Inhibitors, Databases, Factual, Drug Delivery Systems, Macrocyclic Compounds, Drug Discovery
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