Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection: Miniperspective

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

Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139 · see citing works

Molecular properties that influence the oral bioavailability of drug candidates

Veber, D. F., Johnson, S. R., Cheng, H.-Y., Smith, B. R., Ward, K. W., & Kopple, K. D. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm020017n · Cited by 8,420 · 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

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

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

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

Doak, B. C., Over, B., Giordanetto, F., & Kihlberg, J. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.013 · Cited by 835 · see citing works

Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs

Shultz, M. D. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00686 · Cited by 456 · see citing works

Current strategies for the design of PROTAC linkers: a critical review

Troup, R. I., Fallan, C., & Baud, M. G. J. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00018 · Cited by 424 · see citing works

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

Using the Golden Triangle to optimize clearance and oral absorption

Johnson, T. W., Dress, K. R., & Edwards, M. P. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.08.045 · Cited by 398 · see citing works

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

Defining optimum lipophilicity and molecular weight ranges for drug candidates—Molecular weight dependent lower logD limits based on permeability

Waring, M. J. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.03.109 · Cited by 334 · see citing works

Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation

Chen, Y., Tandon, I., Heelan, W. J., Wang, Y., Tang, W., & Hu, Q. (2022) · Chemical Society Reviews · doi:10.1039/d1cs00762a · Cited by 327 · see citing works

Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity

Young, R. J., Green, D. V. S., Luscombe, C. N., & Hill, A. P. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.06.001 · Cited by 319 · see citing works

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

Drug-Induced Phospholipidosis: Are There Functional Consequences?

Reasor, M. J., & Kacew, S. (2001) · Experimental Biology and Medicine · doi:10.1177/153537020122600903 · Cited by 266 · see citing works

Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective

Pike, A., Williamson, B., Harlfinger, S., Martin, S. W., & McGinnity, D. F. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.07.013 · Cited by 247 · 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

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Kofink, C. C., Trainor, N. B., Mair, B., Wöhrle, S., Wurm, M., Mischerikow, N., Roy, M. J., Bader, G., Greb, P., Garavel, G., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33430-6 · Cited by 239 · see citing works

Bayer’s in silico ADMET platform: a journey of machine learning over the past two decades

Göller, A. H., Kuhnke, L., Montanari, F., Bonin, A., Schneckener, S., ter Laak, A., Wichard, J., Lobell, M., & Hillisch, A. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.07.001 · Cited by 215 · see citing works

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

P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

Seelig, A. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.576559 · Cited by 202 · see citing works

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

Liu, X., Kalogeropulou, A. F., Domingos, S., Makukhin, N., Nirujogi, R. S., Singh, F., Shpiro, N., Saalfrank, A., Sammler, E. M., Ganley, I. G., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c05499 · Cited by 198 · see citing works

Clearance in Drug Design

Smith, D. A., Beaumont, K. C., Maurer, T. S., & Di, L. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01263 · Cited by 193 · see citing works

EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides

Goetz, G. H., Philippe, L., & Shapiro, M. J. (2014) · ACS Medicinal Chemistry Letters · doi:10.1021/ml500239m · Cited by 160 · 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

Facts, Patterns, and Principles in Drug Discovery: Appraising the Rule of 5 with Measured Physicochemical Data

Tinworth, C. P., & Young, R. J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01596 · Cited by 132 · see citing works

High Throughput Method for the Indirect Detection of Intramolecular Hydrogen Bonding

Goetz, G. H., Farrell, W. P., Shalaeva, M. Y., Sciabola, S., Anderson, D. P., Yan, J., Philippe, L., & Shapiro, M. J. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401859b · Cited by 119 · see citing works

Modeling Physico-Chemical ADMET Endpoints with Multitask Graph Convolutional Networks

Montanari, F., Kuhnke, L., ter Laak, A., & Clevert, D.-A. (2019) · Molecules · doi:10.3390/molecules25010044 · Cited by 115 · see citing works

Best of Both Worlds: Combining Pharma Data and State of the Art Modeling Technology To Improve in Silico pKa Prediction

Fraczkiewicz, R., Lobell, M., Göller, A. H., Krenz, U., Schoenneis, R., Clark, R. D., & Hillisch, A. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500585w · Cited by 107 · see citing works

The Critical Role of Passive Permeability in Designing Successful Drugs

Di, L., Artursson, P., Avdeef, A., et al. (2020) · ChemMedChem · doi:10.1002/cmdc.202000419 · Cited by 106 · see citing works

Evaluating the Differences in Cycloalkyl Ether Metabolism Using the Design Parameter “Lipophilic Metabolism Efficiency” (LipMetE) and a Matched Molecular Pairs Analysis

Stepan, A. F., Kauffman, G. W., Keefer, C. E., Verhoest, P. R., & Edwards, M. P. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4008642 · Cited by 101 · see citing works

Prediction of Oral Bioavailability in Rats: Transferring Insights from in Vitro Correlations to (Deep) Machine Learning Models Using in Silico Model Outputs and Chemical Structure Parameters

Schneckener, S., Grimbs, S., Hey, J., Menz, S., Osmers, M., Schaper, S., Hillisch, A., & Göller, A. H. (2019) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.9b00460 · Cited by 95 · see citing works

Mechanism of Action of P-Glycoprotein in Relation to Passive Membrane Permeation

Eytan, G. D., & Kuchel, P. W. (1999) · International review of cytology · doi:10.1016/s0074-7696(08)62148-8 · Cited by 81 · see citing works

Inhibitors of Multidrug Efflux Transporters: Their Membrane and Protein Interactions

Seelig, A., & Gatlik-Landwojtowicz, E. (2005) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557053402693 · Cited by 72 · see citing works

PROTAC Cell Permeability and Oral Bioavailability: A Journey Into Uncharted Territory

Poongavanam, V., & Kihlberg, J. (2022) · Future Medicinal Chemistry · doi:10.4155/fmc-2021-0208 · Cited by 72 · see citing works

Tactics in Contemporary Drug Design

Meanwell, N. A. (2014) · Topics in medicinal chemistry · doi:10.1007/978-3-642-55041-6 · Cited by 70 · see citing works

Degradative transport of cationic amphiphilic drugs across phospholipid bilayers

Baciu, M., Sébaï, S. C., Ces, O., Mulet, X., Clarke, J. A., Shearman, G. C., Law, R. V., Templer, R. H., Plisson, C., Parker, C. A., et al. (2006) · Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rsta.2006.1842 · Cited by 67 · see citing works

Mechanism of multidrug resistance in relation to passive membrane permeation

Eytan, G. D. (2005) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2005.01.003 · Cited by 62 · see citing works

An approach towards enhancement of a screening library: The Next Generation Library Initiative (NGLI) at Bayer — against all odds?

Follmann, M., Briem, H., Steinmeyer, A., Hillisch, A., Schmitt, M. H., Haning, H., & Meier, H. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.12.003 · Cited by 53 · see citing works

Advances in computationally modeling human oral bioavailability

Wang, J., & Hou, T. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.01.001 · Cited by 50 · see citing works

New Approaches to Drug Discovery

Nielsch, U., Fuhrmann, U., & Jaroch, S. (2016) · Handbook of experimental pharmacology · doi:10.1007/978-3-319-28914-4 · Cited by 40 · see citing works

P-glycoprotein substrate transport assessed by comparing cellular and vesicular ATPase activity

Nervi, P., Li‐Blatter, X., Äänismaa, P., et al. (2009) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2009.11.022 · Cited by 36 · see citing works

Prediction of Chameleonic Efficiency

David, L., Wenlock, M. C., Barton, P., & Ritzén, A. (2021) · ChemMedChem · doi:10.1002/cmdc.202100306 · Cited by 34 · see citing works

Leveraging chromatography based physicochemical properties for efficient drug design

Goetz, G. H., & Shalaeva, M. Y. (2018) · ADMET & DMPK · doi:10.5599/admet.529 · Cited by 26 · see citing works

Quantitative structure–permeability relationships at various pH values for acidic and basic drugs and drug-like compounds

Oja, M., & Maran, U. (2015) · SAR and QSAR in environmental research · doi:10.1080/1062936x.2015.1085896 · Cited by 22 · see citing works

LipMetE (Lipophilic Metabolism Efficiency) as a Simple Guide for Half-Life and Dosing Regimen Prediction of Oral Drugs

Cecere, G., Guasch, L., Olivares‐Morales, A., et al. (2022) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.2c00183 · Cited by 17 · see citing works

Permeability Prediction for Zwitterions via Chromatographic Indexes and Classification into ‘Certain’ and ‘Uncertain’

Caudana, F., Ermondi, G., Vallaro, M., Shalaeva, M. Y., & Caron, G. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2019-0071 · Cited by 12 · see citing works

Lysis of membrane lipids promoted by small organic molecules: Reactivity depends on structure but not lipophilicity

Britt, H. M., Prakash, A. S., Appleby, S., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaz8598 · Cited by 11 · see citing works

Metabolic (Hepatic) Clearance

Smith, D. A., Allerton, C. M. N., Kalgutkar, A. S. S., et al. (2012) · Methods and principles in medicinal chemistry · doi:10.1002/9783527645763.ch7 · Cited by 4 · see citing works

Drug–Membrane Permeability across Chemical Space

Menichetti, R., Kanekal, K. H., & Bereau, T. (2019) · ACS Central Science · doi:10.1021/acscentsci.8b00718 · Cited by 2 · see citing works

Artificial Intelligence for Drug Discovery: Are We There Yet?

Hasselgren, C., & Oprea, T. I. (2024) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-040323-040828 · Cited by 236 · see citing works

Drug-like Properties of Some Esters of ortho-/meta-/para-Alkoxyphenylcarbamic Acid Containing N-Phenylpiperazine Fragment

Malík, I. (2014) · Global Journal of Medical Research · Cited by 1 · see citing works

Bioavailability of veterinary drugsin vivoandin silico

Grabowski, T., & JAROSZEWSKI, J. J. (2008) · Journal of Veterinary Pharmacology and Therapeutics · doi:10.1111/j.1365-2885.2008.01034.x · Cited by 18 · see citing works

1‐[(2‐Arylthiazol‐4‐yl)methyl]azoles as a New Class of Anticonvulsants: Design, Synthesis,In vivoScreening, andIn silicoDrug‐like Properties

Ahangar, N., Ayati, A., Alipour, E., et al. (2011) · Chemical Biology & Drug Design · doi:10.1111/j.1747-0285.2011.01211.x · Cited by 61 · see citing works

Rational design-aided discovery of novel 1,2,4-oxadiazole derivatives as potential EGFR inhibitors

Unadkat, V., Rohit, S., Parikh, P. H., Sanna, V. K., & Singh, S. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.105124 · Cited by 13 · see citing works

Toward minimalistic modeling of oral drug absorption

Oprea, T. I., & Gottfries, J. (1999) · Journal of Molecular Graphics and Modelling · doi:10.1016/s1093-3263(99)00034-0 · Cited by 99 · see citing works