Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

Doak, Bradley Croy; Over, Bjӧrn; Giordanetto, Fabrizio; Kihlberg, Jan

doi:10.1016/j.chembiol.2014.08.013

Cited by 869Computational Drug Discovery MethodsDrug Solubulity and Delivery SystemsChemical Synthesis and Analysis

Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

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Doak, Bradley Croy, Over, Bjӧrn, Giordanetto, Fabrizio, Kihlberg, Jan·2014·Chemistry & Biology

DOI 10.1016/j.chembiol.2014.08.013

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Abstract

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 drug development, 500 Da is often quoted as the maximum molecular weight parameter, but molecules with higher molecular weights can be absorbed, and the limits of oral bioavailability appear to extend to about MW ≤ 1000 Da.
“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]
PROTAC physicochemical property space generally falls beyond the rule of 5 owing to the bifunctional nature of the molecules.
“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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Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019
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Principles for targeting RNA with drug-like small molecules
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Advances in oral peptide therapeutics
Drucker, D. J. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0053-0 · Cited by 665 · see citing works
Antibacterial Nanomaterials: Mechanisms, Impacts on Antimicrobial Resistance and Design Principles
Xie, M., Gao, M., Yun, Y. S., Malmsten, M., Rotello, V. M., Zbořil, R., Akhavan, O., Kraskouski, A. N., Amalraj, J., Cai, X., et al. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202217345 · Cited by 510 · see citing works
Rings in Clinical Trials and Drugs: Present and Future
Shearer, J., Castro, J. L., Lawson, A. D. G., MacCoss, M., & Taylor, R. D. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00473 · Cited by 491 · see citing works
Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues
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Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs.
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Orally Absorbed Cyclic Peptides
Nielsen, D. S., Shepherd, N. E., Xu, W., Lucke, A. J., Stoermer, M. J., & Fairlie, D. P. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00838 · Cited by 451 · see citing works
Big Data from Pharmaceutical Patents: A Computational Analysis of Medicinal Chemists’ Bread and Butter
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Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges
Edmondson, S. D., Yang, B., & Fallan, C. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.04.030 · Cited by 422 · see citing works
Alkaloids Used as Medicines: Structural Phytochemistry Meets Biodiversity—An Update and Forward Look
Heinrich, M., Mah, J., & Amirkia, V. (2021) · Molecules · doi:10.3390/molecules26071836 · Cited by 436 · see citing works
“Selecting candidates for drug developments using computational design and empirical rules has resulted in a broad discussion about their success [1].”
Background
Beyond the Rule of 5: Lessons Learned from AbbVie’s Drugs and Compound Collection
DeGoey, D. A., Chen, H.-J., Cox, P. B., & Wendt, M. D. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00717 · Cited by 387 · see citing works
Analysis of the Physicochemical Properties of Acaricides Based on Lipinski's Rule of Five
Chen, X., Li, H., Tian, L., Li, Q., Luo, J., & Zhang, Y. (2020) · Journal of Computational Biology · doi:10.1089/cmb.2019.0323 · Cited by 371 · see citing works
“According to the RO5, a drug-like compound should have a molecular weight (MW) of < 500g/mol, a log p value of < 5 representing its hydrophobicity, no > 5 hydrogen bond donors (HBDs), and no > 10 hydrogen bond acceptor (HBA) sites (Doak et al., 2014).”
Macrocycles in Drug Discovery─Learning from the Past for the Future
Jiménez, D. G., Poongavanam, V., & Kihlberg, J. O. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00134 · Cited by 351 · see citing works
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How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets
Doak, B. C., Zheng, J., Dobritzsch, D., & Kihlberg, J. O. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01286 · Cited by 345 · see citing works
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Oral delivery of macromolecular drugs: Where we are after almost 100 years of attempts
Moroz, E., Matoori, S., & Leroux, J. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.01.010 · Cited by 336 · see citing works
Cell permeability beyond the rule of 5
Matsson, P., Doak, B. C., Over, B., & Kihlberg, J. O. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.03.013 · Cited by 300 · see citing works
Self-citation
How Big Is Too Big for Cell Permeability?
Matsson, P., & Kihlberg, J. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00237 · Cited by 303 · see citing works
Self-citation
Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs
Whitty, A., Zhong, M., Viarengo‐Baker, L. A., Beglov, D., Hall, D. R., & Vajda, S. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.02.005 · Cited by 286 · see citing works
FAF-Drugs3: a web server for compound property calculation and chemical library design
Lagorce, D., Spérandio, O., Baell, J. B., Miteva, M. A., & Villoutreix, B. O. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv353 · Cited by 277 · see citing works
Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors
Lagorce, D., Douguet, D., Miteva, M. A., & Villoutreix, B. O. (2017) · Scientific Reports · doi:10.1038/srep46277 · Cited by 276 · see citing works
Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1
Crew, A. P., Raina, K., Dong, H., Qian, Y., Wang, J., Vigil, D., Serebrenik, Y. V., Hamman, B. D., Morgan, A., Ferraro, C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00635 · Cited by 257 · see citing works
Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space
Meanwell, N. A. (2016) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.6b00043 · Cited by 244 · see citing works
Concepts and Core Principles of Fragment-Based Drug Design
Kirsch, P., Hartman, A. M., Hirsch, A. K. H., & Empting, M. (2019) · Molecules · doi:10.3390/molecules24234309 · Cited by 243 · see citing works
“Importantly, it has to be noted that eventual drugs and clinical candidates can still have good bioavailability, whilst violating the Lipinski rules [19].”
Background
Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5
Sebastiano, M. R., Doak, B. C., Backlund, M., Poongavanam, V., Over, B., Ermondi, G., Caron, G., Matsson, P., & Kihlberg, J. O. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00347 · Cited by 238 · see citing works
Self-citation
Drug metabolites and their effects on the development of adverse reactions: Revisiting Lipinski’s Rule of Five
Chagas, C. M., Moss, S., & Alisaraie, L. (2018) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2018.07.046 · Cited by 235 · see citing works
Lipophilic Permeability Efficiency Reconciles the Opposing Roles of Lipophilicity in Membrane Permeability and Aqueous Solubility
Naylor, M. R., Ly, A. M., Handford, M. J., Ramos, D. P., Pye, C. R., Furukawa, A., Klein, V. G., Noland, R. P., Edmondson, Q. D., Turmon, A. C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01259 · Cited by 211 · see citing works
Structural and conformational determinants of macrocycle cell permeability
Over, B., Matsson, P., Tyrchan, C., Artursson, P., Doak, B. C., Foley, M. A., Hilgendorf, C., Johnston, S. E., Lee, M. D., Lewis, R. J., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2203 · Cited by 209 · see citing works
“6b), eight microstates were defined based on the patterns of intramolecular hydrogen bonds among the protonated amine, carbonyl and hydroxyl functions: (1) NH–OH–O=C, (2) NH–OH–OC, (3) NH–OH, (4) NH–O=C, (5) OH–O=C, (6) NH–OC, (7) OH–OC, (8) no detectable hydrogen bonds.”
BackgroundSelf-citation
Solution Conformations Shed Light on PROTAC Cell Permeability
Atilaw, Y., Poongavanam, V., Svensson Nilsson, C., Nguyen, D., Giese, A., Meibom, D., Erdelyi, M., & Kihlberg, J. (2021) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00556 · Cited by 208 · see citing works
Self-citation
From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation
Cecchini, C., Pannilunghi, S., Tardy, S., & Scapozza, L. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.672267 · Cited by 198 · see citing works
Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets
Naylor, M. R., Bockus, A. T., Blanco, M.-J., & Lokey, R. S. (2017) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2017.04.012 · Cited by 187 · see citing works
“The small group of orally delivered drugs and clinical candidates that lie outside the Ro5 are highly enriched in macrocyclic natural products and derivatives thereof [4 ,10,11].”
Background
Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders
Hornberger, K. R., & Araujo, E. M. V. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00740 · Cited by 186 · see citing works
Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules
Usanov, D. L., Chan, A. I., Maianti, J. P., & Liu, D. R. (2018) · Nature Chemistry · doi:10.1038/s41557-018-0033-8 · Cited by 185 · see citing works
Molecular inflation, attrition and the rule of five
Leeson, P. D. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.01.018 · Cited by 182 · see citing works
Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor
Tanada, M., Tamiya, M., Matsuo, A., Chiyoda, A., Takano, K., Ito, T., Irie, M., Kotake, T., Takeyama, R., Kawada, H., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c03886 · Cited by 181 · see citing works
Macrocycles as protein–protein interaction inhibitors
Dougherty, P. G., Qian, Z., & Pei, D. (2017) · Biochemical Journal · doi:10.1042/bcj20160619 · Cited by 179 · see citing works
“Significant advances have also been made in improving the membrane permeability and oral bioavailability of macrocyclic drugs with analysis of current clinicallyrelevant macrocycles and natural products [29, 30].”
Background
Beyond Cyclosporine A: Conformation-Dependent Passive Membrane Permeabilities of Cyclic Peptide Natural Products
Ahlbach, C., Lexa, K. W., Bockus, A. T., Chen, V., Crews, P., Jacobson, M. P., & Lokey, R. S. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.15.78 · Cited by 179 · see citing works
The Symbiotic Relationship Between Drug Discovery and Organic Chemistry
Grygorenko, O. O., Volochnyuk, D. M., Ryabukhin, S. V., & Judd, D. B. (2019) · Chemistry - A European Journal · doi:10.1002/chem.201903232 · Cited by 172 · see citing works
Fundamental aspects of DMPK optimization of targeted protein degraders
Cantrill, C., Chaturvedi, P., Rynn, C., Schaffland, J. P., Walter, I., & Wittwer, M. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.03.012 · Cited by 169 · see citing works
Developing degraders: principles and perspectives on design and chemical space
Maple, H. J., Clayden, N., Baron, A., Stacey, C., & Felix, R. L. (2019) · MedChemComm · doi:10.1039/c9md00272c · Cited by 159 · see citing works
Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy
Owen, A., & Rannard, S. P. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.02.003 · Cited by 159 · see citing works
“culminated in the biophysical classification system (BCS) and design rules for optimal bioavailability such as Lipinski’s rule of five and its various iterations [18, 19].”
Method
Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers
Cantley, J. L., Ye, X., Rousseau, E., Januario, T., Hamman, B. D., Rose, C. M., Cheung, T. K., Hinkle, T. B., Soto, L., Quinn, C., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34562-5 · Cited by 158 · see citing works
Target-Based Evaluation of “Drug-Like” Properties and Ligand Efficiencies
Leeson, P. D., Bento, A. P., Gaulton, A., Hersey, A., Manners, E. J., Radoux, C. J., & Leach, A. R. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00416 · Cited by 164 · see citing works
Emerging Methods and Design Principles for Cell‐Penetrant Peptides
Peraro, L., & Kritzer, J. A. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201801361 · Cited by 157 · see citing works
Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules
Pye, C. R., Hewitt, W. M., Schwochert, J. A., Haddad, T. D., Townsend, C. E., Etienne, L., Lao, Y., Limberakis, C., Furukawa, A., Mathiowetz, A. M., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01483 · Cited by 154 · see citing works
“23 To determine whether the apparent permeabilities observed in our system are concordant with current physics-based models, we set out to (1) determine their hydrocarbon/water partition coefficients experimentally and (2) account for the decrease in solubility at higher lipophilicities to determine their intrinsic pe…”
Result
Comparative Evaluation of Covalent Docking Tools
Scarpino, A., Ferenczy, G. G., & Keserű, G. M. (2018) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.8b00228 · Cited by 152 · see citing works
Understanding and Improving the Membrane Permeability of VH032-Based PROTACs
Klein, V. G., Townsend, C. E., Testa, A., Zengerle, M., Maniaci, C., Hughes, S. J., Chan, K.-H., Ciulli, A., & Lokey, R. S. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00265 · Cited by 153 · see citing works
Linker-Dependent Folding Rationalizes PROTAC Cell Permeability
Poongavanam, V., Atilaw, Y., Siegel, S., Giese, A., Lehmann, L. E., Meibom, D., Erdélyi, M., & Kihlberg, J. O. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00877 · Cited by 148 · see citing works
Self-citation
Oral Administration of Peptide‐Based Drugs: Beyond Lipinski's Rule
dos Santos, G. B., Ganesan, A., & Emery, F. D. S. (2016) · ChemMedChem · doi:10.1002/cmdc.201600288 · Cited by 147 · see citing works
Drug discovery beyond the rule of 5 - Opportunities and challenges
Doak, B. C., & Kihlberg, J. O. (2016) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2017.1264385 · Cited by 146 · see citing works
Self-citation
Characteristic roadmap of linker governs the rational design of PROTACs
Dong, Y., Ma, T., Xu, T., Feng, Z., Li, Y., Song, L., Yao, X., Ashby, C. R., & Hao, G.-F. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.04.007 · Cited by 146 · see citing works
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Overcoming the Shortcomings of Peptide-Based Therapeutics
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Authors: Doak, B. C., Over, B., Giordanetto, F., & Kihlberg, J.
Affiliations: Uppsala University (SE)
Corresponding author: Kihlberg, Jan
ORCID: Doak, Bradley Croy
Giordanetto, Fabrizio
Kihlberg, Jan
Venue: Chemistry & Biology
Publisher: Elsevier BV
Published: 2014-09
Volume: 21
Issue: 9
Pages: 1115-1142
ISSN: 1074-5521 (ISSN-L)
DOI: 10.1016/j.chembiol.2014.08.013
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 · 2013: 1 · 2012: 1
FWCI: 2.15
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: public-domain
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
Locations: Chemistry & Biology (publishedVersion, public-domain)
PubMed (publishedVersion)
Funders: AstraZeneca
Uppsala Universitet
Topics: Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

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