Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors

Schirmeister, Tanja; Kesselring, Jochen; Jung, Sascha; Schneider, Thomas; Weickert, Anastasia; Becker, Johannes; Lee, Wook; Bamberger, Denise; Wich, Peter; Distler, Ute; Tenzer, Stefan; Johé, Patrick; Hellmich, Ute A.; Engels, Bernd

doi:10.1021/jacs.6b03052

Cited by 68 publications

(92 citation statements)

References 49 publications

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“…11 In case of the halogenated vinylsulfones this leads to covalent reversible inhibition. 12 We envisioned dipeptidyl nitroalkenes as inhibitors for cysteine proteases. Based upon the inhibition mechanism of vinyl sulfones, protonation of the carbanion might be less favored in the case of the arising nitroalkane carbanion since the acidity of the corresponding acid, namely, the nitroalkane, is higher, and thus, the basicity of the carbanion is lower ( Figure 1b).…”

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confidence: 99%

Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain

Latorre

Schirmeister

Kesselring

et al. 2016

ACS Med. Chem. Lett.

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Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with K i values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl nitroalkenes are tightly binding covalent reversible inhibitors.KEYWORDS: Rhodesain, cruzain, inhibitors, Chagas' disease, sleeping sickness T he target proteases of the presented study, rhodesain and cruzain, are parasite proteases, which belong to the papain-family of cysteine proteases.1,2 They are related to human cathepsins.1,2 Rhodesain is expressed by the protozoa Trypanosoma brucei rhodesiense, which causes the African sleeping sickness. 3,6,7 Cruzain is expressed by T. cruzi, the parasite causing Chagas' disease occurring in South and Central America.4,5 Both proteases are essential for the life cycles of the pathogens. Consequently, their inhibition is an important strategy for the treatment of these diseases. 8,9 K11777 (Figure 1a), a dipeptidyl vinyl sulfone, irreversibly inactivates cysteine proteases 10 by conjugate addition of the thiolate of the cysteine at the active site to the double bond. The resulting carbanion is subsequently protonated driving the process thermodynamically to the more stable enzyme− inhibitor complex (Figure 1b).Irreversible inhibitors can give rise to undesired side reactions. Turning dipeptidyl vinyl sulfones into compounds that reversibly react with thiols by introducing thioethers or halogen atoms into the structure has been reported. 11 In case of the halogenated vinylsulfones this leads to covalent reversible inhibition. 12We envisioned dipeptidyl nitroalkenes as inhibitors for cysteine proteases. Based upon the inhibition mechanism of

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confidence: 99%

Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain

Latorre

Schirmeister

Kesselring

et al. 2016

ACS Med. Chem. Lett.

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“…[13] Dieses neuartige Konzept kann zukünftig fürd as rationale Design von Wirkstoffen gegen andere Proteintargets verwendet werden. Wirz eigten, wie ein monofunktionales,k leines Moleküle ine stabile Proteindimerisierung durch intra-und intermonomere Interaktionen induziert.…”

Section: Angewandte Chemieunclassified

“…Potentielle Nachteile hinsichtlich der eingeschränkten Affinitätv erglichen mit prototypischen "Dimerizers" kçnnen durch die kovalent irreversible Natur der Inhibitorbindung an das Zielmoleküla usgeglichen werden. [13] Dieses neuartige Konzept kann zukünftig fürd as rationale Design von Wirkstoffen gegen andere Proteintargets verwendet werden.…”

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Inhibitor‐induzierte Dimerisierung einer essentiellen Oxidoreduktase aus afrikanischen Trypanosomen

Wagner

Brennich

et al. 2019

Angewandte Chemie

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Jedes Jahr fordern durchT rypanosomen und Leishmanien verursachte Infektionen zehntausende Menschenleben. Der Metabolismus dieser einzelligen eukaryoti-schenP arasiten unterscheidet sich von dem des menschlichen Wirts.Daher stellen die parasitären Enzyme vielversprechende Angriffspunkte fürA rzneistoffe dar.T ryparedoxin (Tpx) aus Trypanosoma brucei ist eine essentielle Oxidoreduktase in der parasitären Detoxifizierungskaskade fürH ydroperoxide. Funktionale In-vitro-und In-vivo-Experimente zeigen, dass ein kleiner,selektiver Inhibitor Tpx effizient inhibiert. Mithilfe von Rçntgenkristallographie,S AXS,a nalytischer SEC,S EC-MALS,M D-Simulationen, ITC und NMR-Spektroskopie kçnnen wir zeigen, wie die kovalente Bindung dieses monofunktionalen Inhibitors zu einer Dimerisierung von Tpx führt. Intra-und intermolekulare Inhibitor-Inhibitor-, Protein-Protein-und Inhibitor-Protein-Interaktionen stabilisieren das Dimer.D as Verhalten dieses effizienten antitrypanosomalen Moleküls stellt somit ein hervorragendes Beispiel füre ine chemisch induzierte Dimerisierung durch einen kleinen, monovalenten Liganden dar,w elches füre in zukünftiges Wirkstoffdesign verwendet werden kann.

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“…A step‐wise application of docking and QM calculations as a protocol for the design of covalent ligands has been proposed by Engels and coworkers ,. The focus is not on an actual covalent docking process, but rather on a workflow for customized covalent inhibitors starting from a known inhibitor.…”

Section: Modeling Covalent Bond Formation In Docking Approachesmentioning

confidence: 99%

Docking of Covalent Ligands: Challenges and Approaches

Sotriffer

2018

Molecular Informatics

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Covalent ligands have recently regained considerable attention in drug discovery. The rational design of such ligands, however, is still faced with particular challenges, mostly related to the fact that covalent bond formation is a quantum mechanical phenomenon which cannot adequately be handled by the force fields or empirical approaches typically used for noncovalent protein-ligand interactions. Although the necessity for quantum chemical approaches is clear, they cannot yet routinely be applied on large data sets of ligands or for a broader exploration of binding modes in docking calculations. On the other hand, technical solutions for performing docking calculations with covalent ligands are available, but their scope is normally quite limited. Scoring functions typically neglect the contribution from covalent bond formation completely. In this situation, the question arises how to approach covalent ligands and which methods to choose for their docking and design.

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Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors

Cited by 68 publications

References 49 publications

Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain

Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain

Inhibitor‐induzierte Dimerisierung einer essentiellen Oxidoreduktase aus afrikanischen Trypanosomen

Docking of Covalent Ligands: Challenges and Approaches

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