Twenty years on: the impact of fragments on drug discovery

New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays

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An inhibitor of Bcl-2 family proteins induces regression of solid tumours

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ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

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K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

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Discovering High-Affinity Ligands for Proteins: SAR by NMR

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Crystal structure of the human β2 adrenergic G-protein-coupled receptor

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Ligand efficiency: a useful metric for lead selection

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Enumeration of 166 Billion Organic Small Molecules in the Chemical Universe Database GDB-17

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A ‘Rule of Three’ for fragment-based lead discovery?

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Impact of high-throughput screening in biomedical research

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Structure of a β1-adrenergic G-protein-coupled receptor

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The role of ligand efficiency metrics in drug discovery

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Chemistry: Chemical con artists foil drug discovery

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A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening

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On the attribution and additivity of binding energies

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Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery

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Vemurafenib: the first drug approved for BRAF-mutant cancer

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Molecular Interaction Studies Using Microscale Thermophoresis

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Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state

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Fragment-Based Drug Discovery

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Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

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Druggability Indices for Protein Targets Derived from NMR-Based Screening Data

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Discovery of Small Molecules that Bind to K‐Ras and Inhibit Sos‐Mediated Activation

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Identification and Prediction of Promiscuous Aggregating Inhibitors among Known Drugs

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Fragment-Based Lead Discovery Using X-ray Crystallography

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An Aggregation Advisor for Ligand Discovery

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Molecular obesity, potency and other addictions in drug discovery

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Privileged Molecules for Protein Binding Identified from NMR-Based Screening

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High-throughput assays for promiscuous inhibitors

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The 'rule of three' for fragment-based drug discovery: where are we now?

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Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery

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Discovery of Potent Nonpeptide Inhibitors of Stromelysin Using SAR by NMR

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Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design

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Natural-product-derived fragments for fragment-based ligand discovery

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Fluorine-NMR Experiments for High-Throughput Screening: Theoretical Aspects, Practical Considerations, and Range of Applicability

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Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

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Experiences in fragment-based drug discovery

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Discovery of 4-Amino- N -[(1 S )-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases

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ALARM NMR: A Rapid and Robust Experimental Method To Detect Reactive False Positives in Biochemical Screens

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NMR screening techniques in drug discovery and drug design

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Fragment-based drug discovery using NMR spectroscopy

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NMR-Based Screening of Proteins Containing 13C-Labeled Methyl Groups

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Observations on Screening-Based Research and Some Concerning Trends in the Literature

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Opportunity Knocks: Organic Chemistry for Fragment‐Based Drug Discovery (FBDD)

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Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation

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Molecular complexity and fragment-based drug discovery: ten years on

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Fragment-based screening using X-ray crystallography and NMR spectroscopy

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Biophysical Fragment Screening of the β 1 -Adrenergic Receptor: Identification of High Affinity Arylpiperazine Leads Using Structure-Based Drug Design

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Efficient exploration of chemical space by fragment-based screening

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Fragment-based hit identification: thinking in 3D

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The influence of the 'organizational factor' on compound quality in drug discovery

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Learning from our mistakes: The ‘unknown knowns’ in fragment screening

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A three-stage biophysical screening cascade for fragment-based drug discovery

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Detection of secondary binding sites in proteins using fragment screening

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Six Biophysical Screening Methods Miss a Large Proportion of Crystallographically Discovered Fragment Hits: A Case Study

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From Experimental Design to Validated Hits

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Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation

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An Integrated Approach to Fragment-Based Lead Generation:Philosophy, Strategy and Case Studies from AstraZenecas Drug Discovery Programmes

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Binding or Bending: Distinction of Allosteric Abl Kinase Agonists from Antagonists by an NMR-Based Conformational Assay

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Lessons for fragment library design: analysis of output from multiple screening campaigns

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Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography

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Kinase-targeted libraries: The design and synthesis of novel, potent, and selective kinase inhibitors

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Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function

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Discovery of Tricyclic Indoles That Potently Inhibit Mcl-1 Using Fragment-Based Methods and Structure-Based Design

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Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration

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Compound Design by Fragment‐Linking

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Detecting Allosteric Sites of HIV-1 Reverse Transcriptase by X-ray Crystallographic Fragment Screening

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Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ

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Promiscuous 2-Aminothiazoles (PrATs): A Frequent Hitting Scaffold

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Expanding medicinal chemistry space

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Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein

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Off-Rate Screening (ORS) By Surface Plasmon Resonance. An Efficient Method to Kinetically Sample Hit to Lead Chemical Space from Unpurified Reaction Products

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Parallel Screening of Low Molecular Weight Fragment Libraries: Do Differences in Methodology Affect Hit Identification?

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Entropic Contribution to the Linking Coefficient in Fragment Based Drug Design: A Case Study

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Ligand deconstruction: Why some fragment binding positions are conserved and others are not

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Selectivity of Kinase Inhibitor Fragments

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Tactics in Contemporary Drug Design

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Fragment‐based Drug Discovery Lessons and Outlook

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One Question, Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists

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Ligand-Orientation Based Fragment Selection in STD NMR Screening

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How Are Fragments Optimized? A Retrospective Analysis of 145 Fragment Optimizations

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NMR-Based Quality Control Approach for the Identification of False Positives and False Negatives in High Throughput Screening

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Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

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Practical Aspects of NMR-Based Fragment Screening

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Design and Generation of Highly Diverse Fluorinated Fragment Libraries and their Efficient Screening with Improved 19F NMR Methodology

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Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations

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Non-covalent Small-Molecule Kelch-like ECH-Associated Protein 1–Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Inhibitors and Their Potential for Targeting Central Nervous System Diseases

Pallesen, J. S., Tran, K. T., & Bach, A. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00358 · Cited by 111 · see citing works

DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery

Zhou, Y., Li, C., Peng, J., Xie, L., Meng, L. H., Li, Q., Zhang, J., Li, X., Li, X., Huang, X., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b09277 · Cited by 110 · see citing works

Fragment Linking Strategies for Structure-Based Drug Design

Bancet, A., Raingeval, C., Lomberget, T., Borgne, M. L., Guichou, J., & Krimm, I. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00242 · Cited by 109 · see citing works

Exploring new targets and chemical space with affinity selection-mass spectrometry

Prudent, R., Annis, D. A., Dandliker, P. J., Ortholand, J.-Y., & Roche, D. (2020) · Nature Reviews Chemistry · doi:10.1038/s41570-020-00229-2 · Cited by 104 · see citing works

Gentle, fast and effective crystal soaking by acoustic dispensing

Collins, P. M., Ng, J. T., Talon, R., Nekrosiute, K., Krojer, T. J., Douangamath, A., Brandão-Neto, J., Wright, N. D., Pearce, N. M., & von Delft, F. (2017) · Acta Crystallographica Section D Structural Biology · doi:10.1107/s205979831700331x · Cited by 108 · see citing works

Dengue drug discovery: Progress, challenges and outlook

Lim, S. P. (2018) · Antiviral Research · doi:10.1016/j.antiviral.2018.12.016 · Cited by 105 · see citing works

Emergent synthetic methods for the modular advancement of sp 3 -rich fragments

Caplin, M. J., & Foley, D. J. (2021) · Chemical Science · doi:10.1039/d1sc00161b · Cited by 108 · see citing works

Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines

Grainger, R., Heightman, T. D., Ley, S. V., Lima, F., & Johnson, C. N. (2018) · Chemical Science · doi:10.1039/c8sc04789h · Cited by 107 · see citing works

The nature of ligand efficiency

Kenny, P. W. (2019) · Journal of Cheminformatics · doi:10.1186/s13321-019-0330-2 · Cited by 110 · see citing works

Covalent fragment libraries in drug discovery

Keeley, A. B., Petri, L., Ábrányi‐Balogh, P., & Keserű, G. M. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.03.016 · Cited by 104 · see citing works

Liganding Functional Tyrosine Sites on Proteins Using Sulfur–Triazole Exchange Chemistry

Brulet, J. W., Borne, A. L., Yuan, K., Libby, A. H., & Hsu, K. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c00648 · Cited by 105 · see citing works

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

Li, Q., & Kang, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155262 · Cited by 103 · see citing works

A generative deep learning approach to de novo antibiotic design

Krishnan, A., Anahtar, M. N., Valeri, J. A., Jin, W., Donghia, N. M., Sieben, L., Luttens, A., Zhang, Y., Modaresi, S. M., Hennes, A. D., et al. (2025) · Cell · doi:10.1016/j.cell.2025.07.033 · Cited by 113 · see citing works

Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation

Liu, Z., Tian, B., Chen, H., Wang, P., Brasier, A. R., & Zhou, J. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.04.006 · Cited by 102 · see citing works

The Time and Place for Nature in Drug Discovery

Young, R. J., Flitsch, S. L., Grigalunas, M., Leeson, P. D., Quinn, R. J., Turner, N. J., & Waldmann, H. (2022) · JACS Au · doi:10.1021/jacsau.2c00415 · Cited by 105 · see citing works

A general fragment-based approach to identify and optimize bioactive ligands targeting RNA

Suresh, B. M., Li, W., Zhang, P., Wang, K. W., Yildirim, I., Parker, C. G., & Disney, M. D. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2012217117 · Cited by 100 · see citing works

Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design

O’Reilly, M., Cleasby, A., Davies, T. G., Hall, R. J., Ludlow, R. F., Murray, C. W., Tisi, D., & Jhoti, H. (2019) · Drug Discovery Today · doi:10.1016/j.drudis.2019.03.009 · Cited by 100 · see citing works

Ubiquitin–proteasome system and the role of its inhibitors in cancer therapy

Aliabadi, F., Sohrabi, B., Mostafavi, E., Pazoki–Toroudi, H., & Webster, T. J. (2021) · Open Biology · doi:10.1098/rsob.200390 · Cited by 100 · see citing works

Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells

Offensperger, F., Tin, G., Duran‐Frigola, M., Hahn, E., Dobner, S., Ende, C. W. A., Strohbach, J. W., Rukavina, A., Brennsteiner, V., Ogilvie, K., et al. (2024) · Science · doi:10.1126/science.adk5864 · Cited by 95 · see citing works

Directing evolution: the next revolution in drug discovery?

Davis, A. M., Plowright, A. T., & Valeur, E. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.146 · Cited by 86 · see citing works

Future challenges with DNA-encoded chemical libraries in the drug discovery domain

Zhao, G., Huang, Y., Zhou, Y., Li, Y., & Li, X. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1614559 · Cited by 86 · see citing works

A Strategy to Aminate Pyridines, Diazines, and Pharmaceuticals via Heterocyclic Phosphonium Salts

Patel, C., Mohnike, M., Hilton, M. C., & McNally, A. (2018) · Organic Letters · doi:10.1021/acs.orglett.8b00813 · Cited by 86 · see citing works

Computer-aided drug design in anti-cancer drug discovery: What have we learnt and what is the way forward?

Iwaloye, O., Ottu, P. O., Olawale, F., Babalola, O. O., Elekofehinti, O. O., Kikiowo, B., Adegboyega, A. E., Ogbonna, H. N., Adeboboye, C. F., Folorunso, I. M., et al. (2023) · Informatics in Medicine Unlocked · doi:10.1016/j.imu.2023.101332 · Cited by 88 · see citing works

Current perspectives and trend of computer-aided drug design: a review and bibliometric analysis

Wu, Z., Chen, S., Wang, Y., Li, F., Xu, H., Li, M., Zeng, Y., Wu, Z., & Gao, Y. (2024) · International Journal of Surgery · doi:10.1097/js9.0000000000001289 · Cited by 92 · see citing works

High-Throughput Screening for the Discovery of Enzyme Inhibitors

Lloyd, M. D. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00523 · Cited by 81 · see citing works

In-cell NMR: Why and how?

Theillet, F., & Luchinat, E. (2022) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2022.04.002 · Cited by 82 · see citing works

Fragment-Based Drug Design: From Then until Now, and Toward the Future

Xu, W., & Kang, C. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00424 · Cited by 80 · see citing works

Evolution of commercially available compounds for HTS

Volochnyuk, D. M., Ryabukhin, S. V., Moroz, Y. S., Savych, O., Chuprina, A., Horvath, D., Zabolotna, Y., Varnek, A. A., & Judd, D. B. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.10.016 · Cited by 79 · see citing works

The rise of molecular simulations in fragment-based drug design (FBDD): an overview

Bissaro, M., Sturlese, M., & Moro, S. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.06.023 · Cited by 76 · see citing works

Targeting the MAPK Pathway in RAS Mutant CancersPreprint

Hymowitz, S. G., & Malek, S. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031492 · Cited by 79 · see citing works

Structure-based virtual screening of vast chemical space as a starting point for drug discovery

Carlsson, J., & Luttens, A. (2024) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2024.102829 · Cited by 78 · see citing works

Fragment-to-Lead Medicinal Chemistry Publications in 2018

Erlanson, D. A., de Esch, I. J. P., Jahnke, W., Johnson, C. N., & Mortenson, P. N. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01581 · Cited by 77 · see citing works

Fragment-based drug discovery: opportunities for organic synthesis

Denis, J. D. S., Hall, R. J., Murray, C. W., Heightman, T. D., & Rees, D. C. (2020) · RSC Medicinal Chemistry · doi:10.1039/d0md00375a · Cited by 76 · see citing works

Fragments: where are we now?

Osborne, J., Panova, S., Rapti, M., Urushima, T., & Jhoti, H. (2020) · Biochemical Society Transactions · doi:10.1042/bst20190694 · Cited by 59 · see citing works

Integration of fragment screening and library design

Siegal, G., Eiso, A. B., & Schultz, J. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.08.005 · Cited by 142 · see citing works

Fragment-based drug discovery: A graphical review

AlKharboush, D. F., Kozielski, F., Wells, G., & Porta, E. O. J. (2025) · Current Research in Pharmacology and Drug Discovery · doi:10.1016/j.crphar.2025.100233 · Cited by 24 · see citing works

Application of Fragment-Based Drug Discovery to Versatile Targets

Li, Q. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00180 · Cited by 203 · see citing works

How to Find a Fragment: Methods for Screening and Validation in Fragment‐Based Drug Discovery

Kirkman, T., Silva, C. D. S., Tosin, M., & Dias, M. V. B. (2024) · ChemMedChem · doi:10.1002/cmdc.202400342 · Cited by 24 · see citing works