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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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BackgroundInfluentialTackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics
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Anti-mycobacterial natural products and mechanisms of action
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“Ro5 plays a significant role in prioritizing the compounds with an increased likelihood of high oral absorption in drug discovery process [Doak et al., 2014].”
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Scopy: an integrated negative design python library for desirable HTS/VS database design
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“silico to be non-druggable, efforts are rising to explore compounds in the oral druggable space beyond the rule of five (bRo5) [54, 55].”
BackgroundBioactive Marine Xanthones: A Review
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“Classical rules have many exceptions, and there are many examples, namely among NP or NP-inspired, of successful drugs that violate them [26].”
BackgroundIFITM proteins assist cellular uptake of diverse linked chemotypes
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“…molecular weight therapeutics such as natural products and synthetic macrocycles often comprise highly tailored arrangements of polar/non-polar functionality that allow switching between membrane-favored and aqueous-favored conformations to enable passive permeability through membranes (12).”
Quantifying the hydrogen-bond propensity of drugs and its relationship with Lipinski's rule of five
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Applications of Artificial Intelligence in Drug Design: Opportunities and Challenges
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A new paradigm for navigating compound property related drug attrition
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“The properties like molecular weight less than 500 g/mol, less than 5 numbers of hydrogen bond donors, less than 10 numbers of hydrogen bond acceptors and less than 10 rotatable bonds were chosen as criteria, while the selection of molecules to be synthesized (Doak et al., 2014).”
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Kinetic Target-Guided Synthesis: Reaching the Age of Maturity
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“Key synthetic objectives were defined based on shared properties of many successful small-molecule drugs (43, 44).”
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Learning About Allosteric Drugs and Ways to Design Them
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Theoretical Prediction of Gastrointestinal Absorption of Phytochemicals
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In Silico and In Vitro Analyses to Repurpose Quercetin as a Human Pancreatic α-Amylase Inhibitor
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“72 The Egan rule states that a candidate drug has good oral absorption if − 1.0 ≤ log P ≤ 5.8 and TPSA ≤ 130 Å 2 ; 73 quercetin was found to follow this rule within acceptable log P and TPSA values.”
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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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