A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2016 May 25

PMID 27218427

Citations 577

Authors

Antoine Daina

Vincent Zoete

Affiliations

Soon will be listed here.

Abstract

Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to estimate at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small molecules. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochemical descriptors and straightforwardly translated into molecular design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED-Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.

Citing Articles

Comprehensive overview of the toxicities of small-molecule cryoprotectants for carnivorous spermatozoa: foundation for computational cryobiotechnology.

Karimi I, Mohammad L, Suvitha A, Haidari Z, Schioth H Front Toxicol. 2025; 7:1477822.

PMID: 40078955 PMC: 11897285. DOI: 10.3389/ftox.2025.1477822.

Antifungal Peptides with Unexpected Structure from a Library of Synthetic Analogs of Host-Defense Peptide Rigin.

Porras M, Hernandez D, Boto A Int J Mol Sci. 2025; 26(5).

PMID: 40076526 PMC: 11900302. DOI: 10.3390/ijms26051900.

Investigation of anti-microbial and cytotoxic potential of Streptomyces werraensis GRS9 derived from the sediments of river Ganga.

Malik D, Panwar H, Rani S, Gupta K Braz J Microbiol. 2025; .

PMID: 40064810 DOI: 10.1007/s42770-025-01642-9.

Synthesis, antibacterial activity, in silico ADMET prediction, docking, and molecular dynamics studies of substituted phenyl and furan ring containing thiazole Schiff base derivatives.

Islam M, Saha J, Marufa S, Kundu T, Hossain I, Nishino H PLoS One. 2025; 20(3):e0318999.

PMID: 40063584 PMC: 11892886. DOI: 10.1371/journal.pone.0318999.

Alkaloids from Caliphruria subedentata (Amaryllidaceae) as Regulators of AChE, BuChE, NMDA and GSK3 Activity: An In Vitro and In Silico Approach for Mimicking Alzheimer´s Disease.

Ordonez W, Palomino N, Varela P, Martinez I, Alves L, Giuliatti S Neurochem Res. 2025; 50(2):116.

PMID: 40056267 PMC: 11890331. DOI: 10.1007/s11064-025-04354-6.

References

Rankovic Z . CNS drug design: balancing physicochemical properties for optimal brain exposure. J Med Chem. 2014; 58(6):2584-608. DOI: 10.1021/jm501535r. View

Kwong A, Kauffman R, Hurter P, Mueller P . Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol. 2011; 29(11):993-1003. DOI: 10.1038/nbt.2020. View

Lipinski C, Lombardo F, Dominy B, Feeney P . Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46(1-3):3-26. DOI: 10.1016/s0169-409x(00)00129-0. View

Ertl P, Rohde B, Selzer P . Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem. 2000; 43(20):3714-7. DOI: 10.1021/jm000942e. View

Ward S, Harries M, Aldegheri L, Andreotti D, Ballantine S, Bax B . Discovery of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a novel clinical AMPA receptor positive modulator. J Med Chem. 2010; 53(15):5801-12. DOI: 10.1021/jm1005429. View

Newby D, Freitas A, Ghafourian T . Decision trees to characterise the roles of permeability and solubility on the prediction of oral absorption. Eur J Med Chem. 2014; 90:751-65. DOI: 10.1016/j.ejmech.2014.12.006. View

Jorgensen W . The many roles of computation in drug discovery. Science. 2004; 303(5665):1813-8. DOI: 10.1126/science.1096361. View

Egan W, Lauri G . Prediction of intestinal permeability. Adv Drug Deliv Rev. 2002; 54(3):273-89. DOI: 10.1016/s0169-409x(02)00004-2. View

Ghose A, Herbertz T, Hudkins R, Dorsey B, Mallamo J . Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery. ACS Chem Neurosci. 2012; 3(1):50-68. PMC: 3260741. DOI: 10.1021/cn200100h. View

10.

Tian S, Wang J, Li Y, Li D, Xu L, Hou T . The application of in silico drug-likeness predictions in pharmaceutical research. Adv Drug Deliv Rev. 2015; 86:2-10. DOI: 10.1016/j.addr.2015.01.009. View

11.

Egan W, Merz Jr K, Baldwin J . Prediction of drug absorption using multivariate statistics. J Med Chem. 2000; 43(21):3867-77. DOI: 10.1021/jm000292e. View

12.

Gaur S, Torabi A, Corral J . Isolated central nervous system relapse in two patients with BCR-ABL-positive acute leukemia while receiving a next-generation tyrosine kinase inhibitor. In Vivo. 2014; 28(6):1149-53. View

13.

Sugano K, Kansy M, Artursson P, Avdeef A, Bendels S, Di L . Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov. 2010; 9(8):597-614. DOI: 10.1038/nrd3187. View

14.

Di L, Artursson P, Avdeef A, Ecker G, Faller B, Fischer H . Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discov Today. 2012; 17(15-16):905-12. DOI: 10.1016/j.drudis.2012.03.015. View

15.

Huang W, Metcalf C, Sundaramoorthi R, Wang Y, Zou D, Thomas R . Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase.... J Med Chem. 2010; 53(12):4701-19. DOI: 10.1021/jm100395q. View

16.

Kubinyi H . Drug research: myths, hype and reality. Nat Rev Drug Discov. 2003; 2(8):665-8. DOI: 10.1038/nrd1156. View

17.

Daina A, Zoete V . A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem. 2016; 11(11):1117-21. PMC: 5089604. DOI: 10.1002/cmdc.201600182. View

18.

Waring M, Arrowsmith J, Leach A, Leeson P, Mandrell S, Owen R . An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov. 2015; 14(7):475-86. DOI: 10.1038/nrd4609. View

19.

Brito-Sanchez Y, Marrero-Ponce Y, Barigye S, Yaber-Goenaga I, Morell Perez C, Le-Thi-Thu H . Towards Better BBB Passage Prediction Using an Extensive and Curated Data Set. Mol Inform. 2016; 34(5):308-30. DOI: 10.1002/minf.201400118. View

20.

Lakshminarayana S, Huat T, Ho P, Manjunatha U, Dartois V, Dick T . Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents. J Antimicrob Chemother. 2015; 70(3):857-67. PMC: 7714050. DOI: 10.1093/jac/dku457. View