Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1
Abstract
Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A clogP value of 4.7 typically results in low aqueous solubility and high metabolic clearance.
“which typically results in low aqueous solubility and high metabolic clearance (Lipinski et al., 2001).”
From A Fungal-Selective Cytochrome bc1 Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance (2016) · cites this paper as Lipinski et al., 2001
L1 and L2 satisfy Lipinski's rules for BBB penetration and calculated logBB values, suggesting they should be capable of crossing the BBB.
“Considering the restrictive Lipinski’s rules for BBB penetration (MW ≤ 450, clogP ≤5, hydrogen bond donors ≤ 5, hydrogen bond acceptors ≤ 10, polar surface area ≤ 90 Å2) and the calculated logBB values (Table S2), both L1 and L2 satisfy these requirements, suggesting that these compounds should be capable of crossing the BBB.”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [75]
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 [59]
Cites
Solvents and Solvent Effects in Organic Chemistry
Reichardt, C. L. (2002) · Wiley eBooks · doi:10.1002/3527601791 · Cited by 5,795 · see citing works
Abraham, M. H. (1993) · Chemical Society Reviews · doi:10.1039/cs9932200073 · Cited by 2,124 · see citing works
Are Crystal Structures Predictable?
Gavezzotti, A. (1994) · Accounts of Chemical Research · doi:10.1021/ar00046a004 · Cited by 922 · see citing works
The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatography
Abraham, M. H., & McGowan, J. C. (1987) · Chromatographia · doi:10.1007/bf02311772 · Cited by 874 · see citing works
Abraham, M. H., Chadha, H. S., Whiting, G. S., & Mitchell, R. C. (1994) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600830806 · Cited by 761 · see citing works
Calculating log Poct from structures
Leo, A. J. (1993) · Chemical Reviews · doi:10.1021/cr00020a001 · Cited by 705 · see citing works
Solubility and partitioning I: Solubility of nonelectrolytes in water
Yalkowsky, S. H., & Valvani, S. C. (1980) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600690814 · Cited by 581 · see citing works
Functional group contributions to drug-receptor interactions
Andrews, P. R., Craik, D. J., & Martin, J. L. (1984) · Journal of Medicinal Chemistry · doi:10.1021/jm00378a021 · Cited by 538 · see citing works
Simple Method of Calculating Octanol/Water Partition Coefficient.
MORIGUCHI, I., Hirono, S., Qian, L. I. U., Nakagome, I., & MATSUSHITA, Y. (1992) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.40.127 · Cited by 536 · see citing works
Abraham, M. H. (1993) · Journal of Physical Organic Chemistry · doi:10.1002/poc.610061204 · Cited by 354 · see citing works
Hydrogen Bonding. 33. Factors That Influence the Distribution of Solutes between Blood and Brain
Abraham, M. H., Chadha, H. S., & Mitchell, R. C. (1994) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600830915 · Cited by 302 · see citing works
Working Group IV: lipids and the immune system. Report and recommendations.
Newberne, P. M., & Thurman, G. B. (1981) · PubMed · Cited by 291 · see citing works
Comparison of Reliability of log P Values for Drugs Calculated by Several Methods.
MORIGUCHI, I., Hirono, S., Nakagome, I., & Hirano, H. (1994) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.42.976 · Cited by 280 · see citing works
Transport of small molecules through the blood-brain barrier: biology and methodology
Pardridge, W. M. (1995) · Advanced Drug Delivery Reviews · doi:10.1016/0169-409x(95)00003-p · Cited by 279 · see citing works
Design principles for orally bioavailable drugs
Navia, M. A., & Chaturvedi, P. R. (1996) · Drug Discovery Today · doi:10.1016/1359-6446(96)10020-9 · Cited by 203 · see citing works
In vitro systems for studying intestinal drug absorption
Hillgren, K. M., Kato, A., & Borchardt, R. T. (1995) · Medicinal Research Reviews · doi:10.1002/med.2610150202 · Cited by 183 · see citing works
Lipophilicity in Molecular Modeling
Testa, B., Carrupt, P., Gaillard, P., Billois, F., & Weber, P. B. (1996) · Pharmaceutical Research · doi:10.1023/a:1016024005429 · Cited by 164 · see citing works
Bodor, N. S., Huang, M., & Harget, A. J. (1994) · Journal of Molecular Structure THEOCHEM · doi:10.1016/0166-1280(94)80078-2 · Cited by 162 · see citing works
Diffusion of Small Non-Electrolytes across Liposome Membranes
Cohen, B., & Bangham, A. (1972) · Nature · doi:10.1038/236173a0 · Cited by 136 · see citing works
Famini, G. R., Penski, C. A., & Wilson, L. Y. (1992) · Journal of Physical Organic Chemistry · doi:10.1002/poc.610050704 · Cited by 131 · see citing works
Murray, J. S., & Politzer, P. A. (1991) · The Journal of Organic Chemistry · doi:10.1021/jo00023a045 · Cited by 130 · see citing works
Murray, J. S., Ranganathan, S., & Politzer, P. A. (1991) · The Journal of Organic Chemistry · doi:10.1021/jo00011a060 · Cited by 118 · see citing works
Abraham, M. H., Chadha, H. S., & Leo, A. J. (1994) · Journal of Chromatography A · doi:10.1016/0021-9673(94)00686-5 · Cited by 114 · see citing works
Complete Thermodynamic Description of H‐Bonding in the Framework of Multiplicative Approach
Raevsky, O. A., Grigorev, V. Y., Kireev, D., & Zefirov, N. S. (1992) · Quantitative Structure-Activity Relationships · doi:10.1002/qsar.19920110109 · Cited by 114 · see citing works
A New Predictive Equation for the Solubility of Drugs Based on the Thermodynamics of Mobile Disorder
Ruelle, P., Rey‐Mermet, C., Buchmann, M., Nam‐Trân, H., Kesselring, U. W., & Huyskens, P. (1991) · Pharmaceutical Research · doi:10.1023/a:1015891126287 · Cited by 108 · see citing works
Neural network studies. 1. Estimation of the aqueous solubility of organic compounds
Bodor, N. S., Harget, A. J., & Huang, M. J. (1991) · Journal of the American Chemical Society · doi:10.1021/ja00025a009 · Cited by 108 · see citing works
Melting Point, Boiling Point, and Symmetry
Abramowitz, R., & Yalkowsky, S. H. (1990) · Pharmaceutical Research · doi:10.1023/a:1015949907825 · Cited by 103 · see citing works
Myrdal, P. B., Manka, A. M., & Yalkowsky, S. H. (1995) · Chemosphere · doi:10.1016/0045-6535(95)00026-5 · Cited by 100 · see citing works
Chapter 33. Recent Advances in the Generation of Molecular Diversity
Moos, W. H., Green, G. D., & Pavia, M. R. (1993) · Annual reports in medicinal chemistry · doi:10.1016/s0065-7743(08)60903-3 · Cited by 99 · see citing works
Suzuki, T. (1991) · Journal of Computer-Aided Molecular Design · doi:10.1007/bf00129753 · Cited by 89 · see citing works
The molecular properties governing solubilities of organic nonelectrolytes in water
Taft, R. W., Abraham, M. H., Doherty, R. M., & Kamlet, M. J. (1985) · Nature · doi:10.1038/313384a0 · Cited by 88 · see citing works
A new method for the estimation of the aqueous solubility of organic compounds
Bodor, N. S., & Huang, M. (1992) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600810924 · Cited by 83 · see citing works
Prediction of Aqueous Solubility of Organic Compounds
Nelson, T. M., & Jurs, P. C. (1994) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci00019a019 · Cited by 83 · see citing works
Applications of small-molecule combinatorial chemistry to drug discovery
Patel, D. V., & Gordon, E. M. (1996) · Drug Discovery Today · doi:10.1016/1359-6446(96)89062-3 · Cited by 74 · see citing works
Brinck, T., Murray, J. S., & Politzer, P. A. (1993) · The Journal of Organic Chemistry · doi:10.1021/jo00077a028 · Cited by 73 · see citing works
Prediction of carbazole solubility and its dependence upon the solvent nature
Ruelle, P., Sarraf, É., & Kesselring, U. W. (1994) · International Journal of Pharmaceutics · doi:10.1016/0378-5173(94)90187-2 · Cited by 60 · see citing works
A Non‐aqueous Partitioning System for Predicting the Oral Absorption Potential of Peptides
Paterson, D. A., Conradi, R. A., Hilgers, A. R., Vidmar, T. J., & Burton, P. S. (1994) · Quantitative Structure-Activity Relationships · doi:10.1002/qsar.19940130103 · Cited by 57 · see citing works
Estimation of the aqueous solubility of complex organic compounds
Yalkowsky, S. H. (1993) · Chemosphere · doi:10.1016/0045-6535(93)90179-9 · Cited by 49 · see citing works
H‐Bond Contribution to Octanol‐Water Partition Coefficients of Polar Compounds
Raevsky, O. A., Schaper, K. ‐., & Seydel, J. K. (1995) · Quantitative Structure-Activity Relationships · doi:10.1002/qsar.19950140504 · Cited by 46 · see citing works
Molecular Symmetry and Related Properties
Dannenfelser, R., Surendran, N., & Yalkowsky, S. H. (1993) · SAR and QSAR in environmental research · doi:10.1080/10629369308029892 · Cited by 45 · see citing works
Analysis of Solute/Solvent Interactions for the Acidity of Acetic Acids by Theoretical Descriptors
Headley, A. D., Starnes, S. D., Wilson, L. Y., & Famini, G. R. (1994) · The Journal of Organic Chemistry · doi:10.1021/jo00105a020 · Cited by 43 · see citing works
Strategies and recent technologies in drug discovery.
Kubinyi, H. (1995) · PubMed · Cited by 43 · see citing works
Combinatorial Approaches Provide Fresh Leads for Medicinal Chemistry
BAUM, R. M. (1994) · Chemical & Engineering News · doi:10.1021/cen-v072n006.p020 · Cited by 40 · see citing works
Chow, H. ‐. S., Chen, H., Ng, T., Myrdal, P. B., & Yalkowsky, S. H. (1995) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci00026a009 · Cited by 38 · see citing works
Estimation of aqueous solubility and melting point of PCB congeners
Abramowitz, R., & Yalkowsky, S. H. (1990) · Chemosphere · doi:10.1016/0045-6535(90)90142-g · Cited by 38 · see citing works
Solubility Predictions for Solid Nitriles and Tertiary Amides Based on the Mobile Order Theory
Ruelle, P., & Kesselring, U. W. (1994) · Pharmaceutical Research · doi:10.1023/a:1018990904867 · Cited by 29 · see citing works
Critique of Recent Comparison of log P Calculation Methods.
Leo, A. J. (1995) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.43.512 · Cited by 24 · see citing works
Kamlet, M. J. (1993) · Progress in physical organic chemistry · doi:10.1002/9780470171981.ch5 · Cited by 15 · see citing works
Estimation of the Aqueous Solubility of Organic Compounds
Yalkowsky, S. H. (1988) · Springer eBooks · doi:10.1007/978-3-642-74140-1_27 · Cited by 11 · see citing works
Flagged first, then by citations
2 of the 51 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691 · see citing works
Daina, A., Michielin, O., & Zoete, V. (2017) · Scientific Reports · doi:10.1038/srep42717 · Cited by 18,367 · see citing works
Lead- and drug-like compounds: the rule-of-five revolution
Lipinski, C. A. (2004) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2004.11.007 · Cited by 6,339 · see citing works
Self-citationPires, D. E. V., Blundell, T. L., & Ascher, D. B. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00104 · Cited by 5,995 · see citing works
TCMSP: a database of systems pharmacology for drug discovery from herbal medicines
Ru, J., Li, P., Wang, J., Zhou, W., Li, B., Huang, C., Li, P., Guo, Z., Tao, W., Yang, Y., et al. (2014) · Journal of Cheminformatics · doi:10.1186/1758-2946-6-13 · Cited by 5,092 · see citing works
ChEMBL: a large-scale bioactivity database for drug discovery
Gaulton, A., Bellis, L. J., Bento, A. P., Chambers, J., Davies, M., Hersey, A., Light, Y., McGlinchey, S., Michalovich, D., Al-Lazikani, B., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gkr777 · Cited by 4,382 · see citing works
Docking and scoring in virtual screening for drug discovery: methods and applications
Kitchen, D. B., Decornez, H. Y., Furr, J. R., & Bajorath, J. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1549 · Cited by 4,245 · see citing works
Drug-like properties and the causes of poor solubility and poor permeability
Lipinski, C. A. (2000) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/s1056-8719(00)00107-6 · Cited by 3,776 · see citing works
Self-citationTargeting multidrug resistance in cancer
Szakács, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., & Gottesman, M. M. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd1984 · Cited by 3,609 · see citing works
How many drug targets are there?
Overington, J. P., Al-Lazikani, B., & Hopkins, A. L. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2199 · Cited by 3,505 · see citing works
PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works
Hopkins, A. L., & Groom, C. R. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd892 · Cited by 3,305 · see citing works
Ertl, P., Rohde, B., & Selzer, P. M. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm000942e · Cited by 3,149 · see citing works
Improved protein–ligand docking using GOLD
Verdonk, M. L., Cole, J. C., Hartshorn, M. J., Murray, C. W., & Taylor, R. D. (2003) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.10465 · Cited by 3,073 · see citing works
Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh, C., Yin, M., Zeng, X., Wu, C., Lü, A., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab255 · Cited by 2,963 · see citing works
Principles of early drug discovery
Hughes, J., Rees, S., Kalindjian, S., & Philpott, K. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01127.x · Cited by 2,859 · see citing works
Plant Polyphenols: Chemical Properties, Biological Activities, and Synthesis
Quideau, S., Deffieux, D., Douat, C., & Pouységu, L. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201000044 · Cited by 2,753 · see citing works
The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates
Roughley, S. D., & Jordan, A. M. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200187y · Cited by 2,740 · see citing works
Molecular Docking and Structure-Based Drug Design Strategies
Ferreira, L. L. G., dos Santos, R. N., Oliva, G., & Andricopulo, A. D. (2015) · Molecules · doi:10.3390/molecules200713384 · Cited by 2,642 · see citing works
A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules
Daina, A., & Zoete, V. (2016) · ChemMedChem · doi:10.1002/cmdc.201600182 · Cited by 2,637 · see citing works
The re-emergence of natural products for drug discovery in the genomics era
Harvey, A. L., Edrada‐Ebel, R., & Quinn, R. J. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4510 · Cited by 2,601 · see citing works
Taylor, R. D., MacCoss, M., & Lawson, A. D. G. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm4017625 · Cited by 2,582 · see citing works
The evolving role of natural products in drug discovery
Koehn, F. E., & Carter, G. T. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1657 · Cited by 2,579 · see citing works
ZINC: A Free Tool to Discover Chemistry for Biology
Irwin, J. J., Sterling, T., Mysinger, M. M., Bolstad, E. S. D., & Coleman, R. G. (2012) · Journal of Chemical Information and Modeling · doi:10.1021/ci3001277 · Cited by 2,533 · see citing works
Drugs for bad bugs: confronting the challenges of antibacterial discovery
Payne, D. J., Gwynn, M. N., Holmes, D. J., & Pompliano, D. L. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2201 · Cited by 2,512 · see citing works
The influence of drug-like concepts on decision-making in medicinal chemistry
Leeson, P. D., & Springthorpe, B. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2445 · Cited by 2,403 · see citing works
Quantifying the chemical beauty of drugs
Bickerton, G. R., Paolini, G. V., Besnard, J., Mureşan, S., & Hopkins, A. L. (2012) · Nature Chemistry · doi:10.1038/nchem.1243 · Cited by 2,301 · see citing works
Antibacterial drug discovery in the resistance era
Brown, E. D., & Wright, G. D. (2016) · Nature · doi:10.1038/nature17042 · Cited by 2,264 · see citing works
Computational systems biology.
Kitano, H. (2002) · Nature · doi:10.1038/nature01254 · Cited by 2,209 · see citing works
Computational Methods in Drug Discovery
Sliwoski, G. R., Kothiwale, S., Meiler, J., & Lowe, E. W. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.007336 · Cited by 2,226 · see citing works
Trends in peptide drug discovery
Muttenthaler, M., King, G. F., Adams, D. J., & Alewood, P. F. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-00135-8 · Cited by 2,022 · see citing works
Prediction of Drug Absorption Using Multivariate Statistics
Egan, W. J., Merz, K. M., & Baldwin, J. J. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm000292e · Cited by 2,015 · see citing works
Cyclodextrin-based pharmaceutics: past, present and future
Davis, M. E., & Brewster, M. E. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1576 · Cited by 2,002 · see citing works
Wolber, G., & Langer, T. (2004) · Journal of Chemical Information and Modeling · doi:10.1021/ci049885e · Cited by 1,989 · see citing works
Diagnosing the decline in pharmaceutical R&D efficiency
Scannell, J. W., Blanckley, A., Boldon, H., & Warrington, B. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3681 · Cited by 1,981 · see citing works
Reaching for high-hanging fruit in drug discovery at protein–protein interfaces
Wells, J. A., & McClendon, C. L. (2007) · Nature · doi:10.1038/nature06526 · Cited by 1,963 · see citing works
Micellar Nanocarriers: Pharmaceutical Perspectives
Torchilin, V. P. (2006) · Pharmaceutical Research · doi:10.1007/s11095-006-9132-0 · Cited by 1,910 · see citing works
Ligand efficiency: a useful metric for lead selection
Hopkins, A. L., Groom, C. R., & Alex, A. (2004) · Drug Discovery Today · doi:10.1016/s1359-6446(04)03069-7 · Cited by 1,895 · see citing works
ADMET in silico modelling: towards prediction paradise?
Waterbeemd, H. V. D., & Gifford, E. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1032 · Cited by 1,894 · see citing works
Cyclodextrins as pharmaceutical solubilizers
Brewster, M. E., & Loftsson, Þ. (2007) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2007.05.012 · Cited by 1,892 · see citing works
Reoptimization of MDL Keys for Use in Drug Discovery
Durant, J. L., Leland, B. A., Henry, D. R., & Nourse, J. G. (2002) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci010132r · Cited by 1,886 · see citing works
Discovery and development of sorafenib: a multikinase inhibitor for treating cancer
Wilhelm, S. M., Carter, C., Lynch, M. J., Lowinger, T. B., Dumas, J., Smith, R. A., Schwartz, B. E., Simantov, R., & Kelley, S. L. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2130 · Cited by 1,826 · see citing works
Cyclodextrins and their pharmaceutical applications
Loftsson, Þ., & Duchêne, D. (2006) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2006.10.044 · Cited by 1,766 · see citing works
Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore
Fleming, F. F., Yao, L., Ravikumar, P. C., Funk, L. A., & Shook, B. C. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm100762r · Cited by 1,764 · see citing works
Strategies to Address Low Drug Solubility in Discovery and Development
Williams, H. D., Trevaskis, N. L., Charman, S. A., Shanker, R. M., Charman, W. N., Pouton, C. W., & Porter, C. J. H. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.005660 · Cited by 1,582 · see citing works
Hazelwood, L. A., Daran, J.-M. G., van Maris, A. J. A., Pronk, J. T., & Dickinson, J. R. (2008) · Applied and Environmental Microbiology · doi:10.1128/aem.02625-07 · Cited by 1,573 · see citing works
Medicinal chemical properties of successful central nervous system drugs
Pajouhesh, H., & Lenz, G. R. (2005) · NeuroRx · doi:10.1602/neurorx.2.4.541 · Cited by 1,566 · see citing works
Nanosuspensions in drug delivery
Rabinow, B. E. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1494 · Cited by 1,528 · see citing works
Prediction of Physicochemical Parameters by Atomic Contributions
Wildman, S. A., & Crippen, G. M. (1999) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci990307l · Cited by 1,491 · see citing works
The ChEMBL bioactivity database: an update
Bento, A. P., Gaulton, A., Hersey, A., Bellis, L. J., Chambers, J. K., Davies, M., Krüger, F. A., Light, Y., Mak, L., McGlinchey, S., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1031 · Cited by 1,487 · see citing works
Synthetic therapeutic peptides: science and market
Vlieghe, P., Lisowski, V., Martínez, J., & Khrestchatisky, M. (2009) · Drug Discovery Today · doi:10.1016/j.drudis.2009.10.009 · Cited by 1,487 · see citing works
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works
Pharmaceuticals as emerging contaminants and their removal from water. A review
Rivera-Utrilla, J., Sánchez-Polo, M., Ferro-García, M. Á., Prados-Joya, G., & Ocampo-Pérez, R. (2013) · Chemosphere · doi:10.1016/j.chemosphere.2013.07.059 · Cited by 1,486 · see citing works
Platforms for antibiotic discovery
Lewis, K. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd3975 · Cited by 1,449 · see citing works
The current state and future directions of RNAi-based therapeutics
Setten, R. L., Rossi, J. J., & Han, S.-P. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0017-4 · Cited by 1,443 · see citing works
Salt formation to improve drug solubility
Serajuddin, A. T. M. (2007) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2007.05.010 · Cited by 1,443 · see citing works
Virtual screening of chemical libraries
Shoichet, B. K. (2004) · Nature · doi:10.1038/nature03197 · Cited by 1,425 · see citing works
Solubilizing Excipients in Oral and Injectable Formulations
Strickley, R. G. (2004) · Pharmaceutical Research · doi:10.1023/b:pham.0000016235.32639.23 · Cited by 1,417 · see citing works
Targeting virulence: a new paradigm for antimicrobial therapy
Clatworthy, A. E., Pierson, E. R., & Hung, D. T. (2007) · Nature Chemical Biology · doi:10.1038/nchembio.2007.24 · Cited by 1,410 · see citing works
Wu, C.-Y., & Benet, L. Z. (2005) · Pharmaceutical Research · doi:10.1007/s11095-004-9004-4 · Cited by 1,401 · see citing works
The exploration of macrocycles for drug discovery — an underexploited structural class
Driggers, E. M., Hale, S. P., Lee, J., & Terrett, N. K. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2590 · Cited by 1,389 · see citing works
Deep reinforcement learning for de novo drug design
Popova, M., Isayev, O., & Tropsha, A. (2018) · Science Advances · doi:10.1126/sciadv.aap7885 · Cited by 1,379 · see citing works
Challenges of Antibacterial Discovery
Silver, L. L. (2011) · Clinical Microbiology Reviews · doi:10.1128/cmr.00030-10 · Cited by 1,376 · see citing works
The Concept of Synthetic Lethality in the Context of Anticancer Therapy
Kaelin, W. G. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1691 · Cited by 1,369 · see citing works
A ‘Rule of Three’ for fragment-based lead discovery?
Congreve, M., Carr, R. A. E., Murray, C. W., & Jhoti, H. (2003) · Drug Discovery Today · doi:10.1016/s1359-6446(03)02831-9 · Cited by 1,365 · see citing works
Principles and Applications of Halogen Bonding in Medicinal Chemistry and Chemical Biology
Wilcken, R., Zimmermann, M. O., Lange, A., Joerger, A. C., & Boeckler, F. M. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3012068 · Cited by 1,364 · see citing works
The evolution of commercial drug delivery technologies
Vargason, A. M., Anselmo, A. C., & Mitragotri, S. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00698-w · Cited by 1,361 · see citing works
The ErbB/HER family of protein-tyrosine kinases and cancer
Roskoski, R. J. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2013.11.002 · Cited by 1,365 · see citing works
Halogen Bonding in Supramolecular Chemistry
Gilday, L. C., Robinson, S. W., Barendt, T. A., Langton, M. J., Mullaney, B. R., & Beer, P. D. (2015) · Chemical Reviews · doi:10.1021/cr500674c · Cited by 1,343 · see citing works
Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity
Ruijter, E., Scheffelaar, R., & Orrù, R. V. A. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201006515 · Cited by 1,332 · see citing works
Metallodrugs in Medicinal Inorganic Chemistry
Mjos, K. D., & Orvig, C. (2014) · Chemical Reviews · doi:10.1021/cr400460s · Cited by 1,311 · see citing works
Pouton, C. W. (2006) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2006.04.016 · Cited by 1,306 · see citing works
Targeting bromodomains: epigenetic readers of lysine acetylation
Filippakopoulos, P., & Knapp, S. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4286 · Cited by 1,274 · see citing works
PubChem: Integrated Platform of Small Molecules and Biological Activities
Bolton, E., Wang, Y., Thiessen, P. A., & Bryant, S. H. (2008) · Annual reports in computational chemistry · doi:10.1016/s1574-1400(08)00012-1 · Cited by 1,267 · see citing works
Nanosizing: a formulation approach for poorly-water-soluble compounds
Merisko-Liversidge, E. M., Liversidge, G. G., & Cooper, E. R. (2003) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(02)00251-8 · Cited by 1,259 · see citing works
Current Contributions of Organofluorine Compounds to the Agrochemical Industry
Ogawa, Y., Tokunaga, E., Kobayashi, O., Hirai, K., & Shibata, N. (2020) · iScience · doi:10.1016/j.isci.2020.101467 · Cited by 1,253 · see citing works
Designed Multiple Ligands. An Emerging Drug Discovery Paradigm
Morphy, R., & Ranković, Z. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058225d · Cited by 1,237 · see citing works
Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances
Lionta, E., Spyrou, G. M., Vassilatis, D. K., & Cournia, Z. (2014) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026614666140929124445 · Cited by 1,220 · see citing works
Kawabata, Y., Wada, K., Nakatani, M., Yamada, S., & Onoue, S. (2011) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2011.08.032 · Cited by 1,194 · see citing works
The role of ligand efficiency metrics in drug discovery
Hopkins, A. L., Keserü, G. M., Leeson, P. D., Rees, D. C., & Reynolds, C. H. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4163 · Cited by 1,181 · see citing works
Towards the sustainable discovery and development of new antibiotics
Miethke, M., Pieroni, M., Weber, T., Brönstrup, M., Hammann, P., Halby, L., Arimondo, P. B., Glaser, P., Aigle, B., Bode, H. B., et al. (2021) · Nature Reviews Chemistry · doi:10.1038/s41570-021-00313-1 · Cited by 1,184 · see citing works
Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations
Murphy, M. P., & Smith, R. A. J. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105110 · Cited by 1,173 · see citing works
Alkilani, A. Z., McCrudden, M., & Donnelly, R. F. (2015) · Pharmaceutics · doi:10.3390/pharmaceutics7040438 · Cited by 1,157 · see citing works
Cancer prevention by tea: animal studies, molecular mechanisms and human relevance
Yang, C. S., Wang, X., Lü, G., & Picinich, S. C. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2641 · Cited by 1,153 · see citing works
Overcoming cellular barriers for RNA therapeutics
Dowdy, S. F. (2017) · Nature Biotechnology · doi:10.1038/nbt.3802 · Cited by 1,139 · see citing works
ESOL: Estimating Aqueous Solubility Directly from Molecular Structure
Delaney, J. S. (2004) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci034243x · Cited by 1,137 · see citing works
A decade of fragment-based drug design: strategic advances and lessons learned
Hajduk, P. J., & Greer, J. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2220 · Cited by 1,068 · see citing works
Hit and lead generation: beyond high-throughput screening
Bleicher, K., Böhm, H., Müller, K., & Alanine, A. I. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1086 · Cited by 1,054 · see citing works
The genome of the blood fluke Schistosoma mansoni
Berriman, M., Haas, B. J., LoVerde, P. T., Wilson, R. A., Dillon, G. P., Cerqueira, G. G., Mashiyama, S. T., Al‐Lazikani, B., Andrade, L. F., Ashton, P. D., et al. (2009) · Nature · doi:10.1038/nature08160 · Cited by 1,051 · see citing works
A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening
McGovern, S. L., Caselli, E., Grigorieff, N., & Shoichet, B. K. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm010533y · Cited by 1,048 · see citing works
Martin, Y. C. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm0492002 · Cited by 1,042 · see citing works
Navigating chemical space for biology and medicine
Lipinski, C. A., & Hopkins, A. L. (2004) · Nature · doi:10.1038/nature03193 · Cited by 1,008 · see citing works
Self-citationSolubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals
Babu, N. J., & Nangia, A. K. (2011) · Crystal Growth & Design · doi:10.1021/cg200492w · Cited by 1,007 · see citing works
Daina, A., Michielin, O. A., & Zoete, V. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500467k · Cited by 1,004 · see citing works
Dobson, C. M. (2004) · Nature · doi:10.1038/nature03192 · Cited by 1,003 · see citing works
Chong, C. R., & Sullivan, D. J. (2007) · Nature · doi:10.1038/448645a · Cited by 996 · see citing works
Physiochemical drug properties associated with in vivo toxicological outcomes
Hughes, J. D., Blagg, J., Price, D. A., Bailey, S., DeCrescenzo, G. A., Devraj, R. V., Ellsworth, E. L., Fobian, Y. M., Gibbs, M. E., Gilles, R. W., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.07.071 · Cited by 995 · see citing works
Degradation of Aqueous Pharmaceuticals by Ozonation and Advanced Oxidation Processes: A Review
Ikehata, K., Naghashkar, N. J., & El‐Din, M. G. (2006) · Ozone Science and Engineering · doi:10.1080/01919510600985937 · Cited by 969 · see citing works
Computer-based de novo design of drug-like molecules
Schneider, G., & Fechner, U. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1799 · Cited by 956 · see citing works
The Process of Structure-Based Drug Design
Anderson, A. C. (2003) · Chemistry & Biology · doi:10.1016/j.chembiol.2003.09.002 · Cited by 943 · see citing works
- Authors
- Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J.
- Affiliations
- Pfizer (United States) (US)
- Corresponding author
- Lipinski, Christopher A
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 2001-03
- Volume
- 46
- Issue
- 1-3
- Pages
- 3-26
- ISSN
- 0169-409X (ISSN-L)
- OpenAlex
- W2135732933
- Cited by
- 18,139
- References
- 51
- Citations by year
- 2026: 869 · 2025: 962 · 2024: 1264 · 2023: 1296 · 2022: 1248 · 2021: 1459 · 2020: 1317 · 2019: 945 · 2018: 876 · 2017: 791 · 2016: 790 · 2015: 724 · 2014: 752 · 2013: 741 · 2012: 708
- FWCI
- 19.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Advanced Drug Delivery Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Materials Science › Materials Chemistry › Crystallization and Solubility Studies
- Keywords
- drug solubility, intestinal permeability, Rule of 5, molecular weight, lipophilicity, polymorphism, linear free energy relationships, thermodynamic solubility, solubility prediction, drug absorption
- MeSH terms
- Adsorption, Chemistry, Physical, Computers, Pharmaceutical Preparations, Permeability, Pharmacology, Solubility, Thermodynamics, Chemical Phenomena
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
