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

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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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“Predictions suggest that strict compliance of rule of 5 led to a large number of lost opportunities (Doak et al., 2014).”
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“In fact, there are several examples that are beyond RO5, leading to the proposal of new limits: HBD ≤ 6, HBA ≤ 15, MW ≤ 1000 Da, -2 ≤ logP ≤ 10, PSA ≤ 250 Å2, and NRB ≤ 20 [16].”
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Background
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“35 Furthermore, parameters such as human serum albumin binding (QPlogKhsa), brain-to-blood partition coefficient (QPlogBB), and blood − brain barrier permeability using the MDCK cell model (QPPMDCK) were within the acceptable range for most active compounds.”
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Background
MetaCGRP is a high-precision meta-model for large-scale identification of CGRP inhibitors using multi-view information
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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
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: 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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Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

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