An effective strategy for enhancing the potency and selectivity of initial active molecules consists of covalent bond formation with a nucleophilic residue that is specific to a target of interest where, ideally, there are no off-target interactions [1-3]. The application of such covalent-binding chemical probes has significantly grown in proteome-wide target identification and imaging, as well as in the search for inhibitors with high specificity among related enzymes and enzyme isoforms [4].
Life Chemicals has designed its novel Serine Focused Covalent Inhibitor Library of over 3,800 potential covalent modifiers that could react with serine residues of a drug target either reversibly or irreversibly. The selected small-molecule screening compounds contain the following serine-specific covalent warheads [5-7]:
- acrylamides [8]
- aldehydes [9
- alkylhalides [8
- beta-lactams
- boronic
- carbamates
- chloroacetyls [8
- epoxides [8
- maleimides [17
- nitroalkenes [19]
- phosphoric compounds [12]
- trifluoromethyl alcohols/ketones [13]
- sulfonyl acrylonitriles [18]
- ureas [15]
- vinyl sulfones [8]
- others
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Compound selection
The covalently binding molecules were selected based on a combination of specific structural fragments (functional groups or “warheads”) that were reported to form covalent bonds with a serine residue in binding sites of proteins [5-7]and drug-like filters. Initially, over 25,000 potential serine covalent inhibitors were picked out from the proprietary HTS Compound Collection and added to the main Covalent Screening Library.
Subsequent narrowing-down by structural diversity filtering resulted in 3,800 serine covalent binders presented in this Screening Set. These structurally-diverse screening compounds were optimized in terms of reactivity and essential stability, being compliant with the in-house MedChem and PAINS structural filters to make them a perfect starting point for covalent screening efforts in drug discovery.
Figure 1. Compound distribution by different chemical classes within the Library.
Representative compounds from the Serine Focused Covalent Inhibitor Library
References:
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- Sgrignani J., Novati B., Colombo G., Grazioso G. Covalent docking of selected boron-based serine beta-lactamase inhibitors. J. Comput. Aided Mol. Des., 2015, 5, 441–50.
- Singh J., Petter R. C., Baillie T. A., Whitty, A. The resurgence of covalent drugs. Nature Rev. Drug Discov., 2011, 10, 307–317.
- Huang F, Zhang B, Zhou S, Zhao X, Bian C, Wei Y. Chemical proteomics: terra incognita for novel drug target profiling. Chin J Cancer. 2012;31(11):507-518.
- Bachovchin D. A., Cravatt B. F. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat. Rev. Drug Discov., 2012, 11, 52–68.
- Cognetta A. B., Niphakis M. J., Lee H. C., Martini M. L., Hulce J. J., Cravatt B. F. Selective N-Hydroxyhydantoin Carbamate Inhibitors of Mammalian Serine Hydrolases. Chem. Biol., 2015 Jun 25.
- Hoover H. S., Blankman J. L., Niessen S. Cravatt B. F. Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg. Med. Chem. Lett., 2008, 18, 5838–5841.
- Powers, James C. et al. “Irreversible inhibitors of serine, cysteine, and threonine proteases.” Chemical reviews 102 12 (2002): 4639-750 .
- Zhu L, George S, Schmidt MF, Al-Gharabli SI, Rademann J, Hilgenfeld R. Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease. Antiviral Res. 2011 Nov;92(2):204-12. doi: 10.1016/j.antiviral.2011.08.001. Epub 2011 Aug 11. PMID: 21854807; PMCID: PMC7114241.
- Tsuyoshi Ohba, Eitatsu Ikeda, Jun Wakayama, Hisashi Takei, Irreversible inhibitions of serine proteases by peptidyl allylic halide derivatives,Bioorganic & Medicinal Chemistry Letters, Volume 6, Issue 3, 1996, Pages 219-224,ISSN 0960-894X, https://doi.org/10.1016/0960-894X(95)00592-H.
- Cognetta AB 3rd, Niphakis MJ, Lee HC, Martini ML, Hulce JJ, Cravatt BF. Selective N-Hydroxyhydantoin Carbamate Inhibitors of Mammalian Serine Hydrolases. Chem Biol. 2015;22(7):928-937. doi:10.1016/j.chembiol.2015.05.018
- Maślanka M, Mucha A. Recent Developments in Peptidyl Diaryl Phoshonates as Inhibitors and Activity-Based Probes for Serine Proteases. Pharmaceuticals (Basel). 2019 Jun 10;12(2):86. doi: 10.3390/ph12020086. PMID: 31185654; PMCID: PMC6631691. phosphonates
- Amour A, Reboud-Ravaux M, de Rosny E, et al. Stereoselective synthesis of peptidyl trifluoromethyl alcohols and ketones: inhibitory potency against human leucocyte elastase, cathepsin G, porcine pancreatic elastase and HIV-1 protease. J Pharm Pharmacol. 1998;50(6):593-600. doi:10.1111/j.2042-7158.1998.tb06892.x
- Koutek B, Prestwich GD, Howlett AC, et al. Inhibitors of arachidonoyl ethanolamide hydrolysis. J Biol Chem. 1994;269(37):22937-22940.
- Deng H, Kooijman S, van den Nieuwendijk AM, et al. Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding. J Med Chem. 2017;60(1):428-440. doi:10.1021/acs.jmedchem.6b01482
- Johe P, Jung S, Endres E, et al. Warhead Reactivity Limits the Speed of Inhibition of the Cysteine Protease Rhodesain. ACS Chem Biol. 2021;16(4):661-670. doi:10.1021/acschembio.0c00911
- Search for Inhibitors of Bacterial and Human Protein Kinases among Derivatives of Diazepines[1,4] Annelated with Maleimide and Indole Cycles. Valery N. Danilenko, Alexander Y. Simonov, Sergey A. Lakatosh, Michael H. G. Kubbutat, Frank Totzke, Christoph Schächtele, Sergey M. Elizarov, Olga B. Bekker, Svetlana S. Printsevskaya, Yuryi N. Luzikov, Marina I. Reznikova, Alexander A. Shtil, and Maria N. Preobrazhenskaya. Journal of Medicinal Chemistry 2008 51 (24), 7731-7736. DOI: 10.1021/jm800758s
- Bachovchin DA, Zuhl AM, Speers AE, Wolfe MR, Weerapana E, Brown SJ, Rosen H, Cravatt BF. Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1. J Med Chem. 2011 Jul 28;54(14):5229-36. doi: 10.1021/jm200502u. Epub 2011 Jun 30. PMID: 21639134; PMCID: PMC3144155.
- Müller P, Meta M, Meidner JL, Schwickert M, Meyr J, Schwickert K, Kersten C, Zimmer C, Hammerschmidt SJ, Frey A, et al. Investigation of the Compatibility between Warheads and Peptidomimetic Sequences of Protease Inhibitors—A Comprehensive Reactivity and Selectivity Study. International Journal of Molecular Sciences. 2023; 24(8):7226. https://doi.org/10.3390/ijms24087226