Technologies for Direct Detection of Covalent Protein–Drug Adducts DOI Creative Commons
Elma Mons, Robbert Q. Kim, Monique P. C. Mulder

et al.

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(4), P. 547 - 547

Published: April 5, 2023

In the past two decades, drug candidates with a covalent binding mode have gained interest of medicinal chemists, as several anticancer drugs successfully reached clinic. As changes relevant parameters to rank inhibitor potency and investigate structure-activity relationship (SAR), it is important gather experimental evidence on existence protein-drug adduct. this work, we review established methods technologies for direct detection adduct, illustrated examples from (recent) development endeavors. These include subjecting mass spectrometric (MS) analysis, protein crystallography, or monitoring intrinsic spectroscopic properties ligand upon adduct formation. Alternatively, chemical modification required detect adducts by NMR analysis activity-based profiling (ABPP). Some techniques are more informative than others can also elucidate modified amino acid residue bond layout. We will discuss compatibility these reversible modes possibilities evaluate reversibility obtain kinetic parameters. Finally, expand current challenges future applications. Overall, analytical present an integral part in exciting new era discovery.

Language: Английский

DNA-Encoded Chemistry: Drug Discovery from a Few Good Reactions DOI
Patrick R. Fitzgerald, Brian M. Paegel

Chemical Reviews, Journal Year: 2020, Volume and Issue: 121(12), P. 7155 - 7177

Published: Oct. 12, 2020

Click chemistry, proposed nearly 20 years ago, promised access to novel chemical space by empowering combinatorial library synthesis with a "few good reactions". These click reactions fulfilled key criteria (broad scope, quantitative yield, abundant starting material, mild reaction conditions, and high chemoselectivity), keeping the focus on molecules that would be easy make, yet structurally diverse. This philosophy bears striking resemblance DNA-encoded (DEL) technology, now-dominant chemistry paradigm. review highlights similarities between DEL design deployment in settings, providing framework for of new technologies enable next-generation drug discovery.

Language: Английский

Citations

163
Recent advances in activity-based probes (ABPs) and affinity-based probes (AfBPs) for profiling of enzymes DOI Creative Commons

Haixiao Fang,

Bo Peng, Sing Yee Ong

et al.

Chemical Science, Journal Year: 2021, Volume and Issue: 12(24), P. 8288 - 8310

Published: Jan. 1, 2021

This review highlights the recent advances in use of activity-based probes (ABPs) and affinity-based (AfBPs), summarizes their design strategies (based on inhibitors substrates) detection approaches.

Language: Английский

Citations

125
Reversible lysine-targeted probes reveal residence time-based kinase selectivity DOI
Tangpo Yang, Adolfo Cuesta, Xiaobo Wan

et al.

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(9), P. 934 - 941

Published: May 19, 2022

Language: Английский

Citations

76
Sulfur(vi) fluorides as tools in biomolecular and medicinal chemistry DOI Creative Commons
Sabrina N. Carneiro, Samuel R. Khasnavis, Jisun Lee

et al.

Organic & Biomolecular Chemistry, Journal Year: 2023, Volume and Issue: 21(7), P. 1356 - 1372

Published: Jan. 1, 2023

This review highlights key advances in the synthesis and biomolecular applications of sulfur( vi )-fluorides.

Language: Английский

Citations

50
Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update DOI

Laura Hillebrand,

Xiaojun Julia Liang,

Ricardo A. M. Serafim

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758

Published: May 7, 2024

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.

Language: Английский

Citations

49
Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable Proteome DOI Creative Commons

Katharine Gilbert,

Aini Vuorinen,

Arron Aatkar

et al.

ACS Chemical Biology, Journal Year: 2023, Volume and Issue: 18(2), P. 285 - 295

Published: Jan. 17, 2023

Here, we report a comprehensive profiling of sulfur(VI) fluorides (SVI-Fs) as reactive groups for chemical biology applications. SVI-Fs are functionalities that modify lysine, tyrosine, histidine, and serine sidechains. A panel were studied with respect to hydrolytic stability reactivity nucleophilic amino acid The use covalently carbonic anhydrase II (CAII) range kinases was then investigated. Finally, the SVI-F used in live cell chemoproteomic workflows, identifying novel protein targets based on type used. This work highlights how can be tool expand liganded proteome.

Language: Английский

Citations

43
Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D DOI Creative Commons
Qinheng Zheng, Ziyang Zhang, Keelan Z. Guiley

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(9), P. 1114 - 1122

Published: March 5, 2024

K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine K-Ras-G12C mutation lock it a signaling-incompetent state. However, covalent inhibition of G12D, frequent particularly prevalent pancreatic ductal adenocarcinoma, has remained elusive due to lack aspartate-targeting chemistry. Here we present set malolactone-based electrophiles that exploit ring strain crosslink K-Ras-G12D at mutant aspartate form stable complexes. Structural insights from X-ray crystallography exploitation stereoelectronic requirements for attack electrophile allowed development substituted malolactone resisted by aqueous buffer but rapidly crosslinked with aspartate-12 both GDP GTP GTP-state targeting effective suppression downstream signaling, selective K-Ras-G12D-driven proliferation vitro xenograft growth mice.

Language: Английский

Citations

34
Comparative Evaluation of Covalent Docking Tools DOI
Andrea Scarpino, György G. Ferenczy, György M. Keserű

et al.

Journal of Chemical Information and Modeling, Journal Year: 2018, Volume and Issue: 58(7), P. 1441 - 1458

Published: June 11, 2018

Increased interest in covalent drug discovery led to the development of computer programs predicting binding mode and affinity inhibitors. Here we compare performance six docking tools, AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, MOE, for reproducing experimental modes an unprecedently large diverse set complexes. It was found that 40–60% top scoring ligand poses are within 2.0 Å RMSD from mode. This rate showed program dependent increase achieved 50–90% when best among ten considered. is comparable noncovalent tools therefore suggests anchoring does not necessarily improve accuracy prediction. The effect various protein features on investigated. At level warhead chemistry, higher success Michael additions, nucleophilic additions substitutions than ring opening reactions disulfide formation. Increasing size flexibility generally affects pose predictions unfavorably, although ICM-Pro were be less sensitive up 35 heavy atoms. accessibility target cysteine tends result improved predictions. Docking show suggesting a target-dependent choice optimal tool. into Cys/Ala mutated proteins by Glide reproduced with only slightly lower at significantly computational expense did. Overall, our results highlight key factors influencing investigated they give guidelines selecting combination warheads, ligands, system Results also identify most important aspects considered developing protocols virtual screening ligands.

Language: Английский

Citations

128
10 Years Into the Resurgence of Covalent Drugs DOI
Elena De Vita

Future Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 13(2), P. 193 - 210

Published: Dec. 4, 2020

In the first decade of targeted covalent inhibition, scientists have successfully reversed previous trend that had impeded use inhibition in drug development. Successes clinic, mainly field kinase inhibitors, are existing proof safe inhibitors can be designed and employed to develop effective treatments. The case KRASG12C entering clinical trials 2019 has been among hottest topics discussed discovery, raising expectations for future field. this perspective, an overview milestones hit with as well promise needs current research, presented. While recent results confirmed potential was foreseen, many questions remain unexplored branch precision medicine.

Language: Английский

Citations

100
A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening DOI Creative Commons
Christoph Gorgulla, Krishna Mohan Das, Kendra E. Leigh

et al.

iScience, Journal Year: 2021, Volume and Issue: 24(2), P. 102021 - 102021

Published: Jan. 10, 2021

The unparalleled global effort to combat the continuing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic over last year has resulted in promising prophylactic measures. However, a need still exists for cheap, effective therapeutics, and targeting multiple points viral life cycle could help tackle current, as well future, coronaviruses. Here, we leverage our recently developed, ultra-large-scale silico screening platform, VirtualFlow, search inhibitors that target SARS-CoV-2. In this unprecedented structure-based virtual campaign, screened roughly 1 billion molecules against each of 40 different sites on 17 potential host targets. addition active enzymes, also targeted critical auxiliary such functionally important protein-protein interactions.

Language: Английский

Citations

86