Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: Improving selectivity over hERG

Rankovic, Zoran; Cai, Jiaqiang; Kerr, Jennifer; Fradera, Xavier; Robinson, John; Mistry, Ashvin; Finlay, William J. J.; McGarry, George; Andrews, Fiona; Caulfield, Wilson; Cumming, Iain; Dempster, Maureen; Waller, John; Arbuckle, Wullie; Anderson, Mark E.; Martin, Iain; Mitchell, Ann; Long, Clive; Baugh, Mark; Westwood, Paul; Kinghorn, Emma; Jones, Phillip W.; Uitdehaag, Joost C.M.; Zeeland, M. van; Potin, Dominique; Sanière, Laurent; Fouquet, Andre; Chevallier, F; Deronzier, Hortense; Dorleans, Cecile; Nicolaï, Eric

doi:10.1016/j.bmcl.2010.08.101

Cited by 8 publications

(3 citation statements)

References 19 publications

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“…In most of the cases, cleavage of the covalent bond followed by local minimization with the MMFF94x force field led to deviations of less than 1 Å; in cases where this value was exceeded, it remained well below 2 Å. Molecules with the warhead attached to a rigid system, such as the aryl nitriles 3KWB, 45 3KWZ, 46 3KW9, 46 3O1G, 47 and 2R6N, 48 showed slightly higher deviations compared to the alkyl nitriles because the former are more restricted in conformational adaptations and required a shift to obtain a reasonable pre-reaction geometry. Complexes 4X6H and 4X6I 49 already contained the ligand in a noncovalent binding mode (cf.…”

Section: ■ Methodsmentioning

confidence: 99%

MD-Based Assessment of Covalent Inhibitors in Noncovalent Association Complexes: Learning from Cathepsin K as a Test Case

Endres

Chen

Sotriffer

2023

J. Chem. Inf. Model.

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A sufficiently stable noncovalent association complex between a covalent inhibitor and its protein target is regarded as a prerequisite for the formation of a covalent complex. As this transient form can hardly be assessed experimentally, computational modeling is required to probe the suitability of a given ligand at this particular stage. To investigate which criteria should be fulfilled by suitable candidates in a molecular dynamics (MD) assessment, a systematic study was conducted with 20 complexes of cathepsin K, a papain-like cysteine protease of pharmaceutical relevance. The covalent inhibitors in these complexes were converted to their pre-reaction states, and the resulting noncovalent complexes were subjected to MD simulations. The critical distance between the electrophilic and nucleophilic reaction partners was monitored as a potential parameter to assess the suitability for covalent bond formation. Across various warhead types, a distance between 3.6 and 4.0 Å, comparable to the sum of the generalized Born radii of carbon and sulfur, was found to be stably maintained under appropriate conditions. The protonation state of the catalytic dyad and the resulting solvation pattern dramatically affected the noncovalent binding mode and the distance of the warhead to the active site. For several complexes, fluctuations in the orientation of the warhead were observed due to torsional rotations in adjacent bonds. This observation helped to explain the gradual transitions from noncovalent to covalent complexes observed in the crystal structures of three closely related nitrile-based inhibitors. According to comparative simulations conducted for a set of 13 cathepsin S complexes, the overall findings of the study appear to be transferable to related cysteine proteases as targets of covalent inhibitors.

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Section: ■ Methodsmentioning

confidence: 99%

MD-Based Assessment of Covalent Inhibitors in Noncovalent Association Complexes: Learning from Cathepsin K as a Test Case

Endres

Chen

Sotriffer

2023

J. Chem. Inf. Model.

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“…Indeed, researchers at Organon, Merck & Co., Inc; One Merck Drive, PO Box 100, Whitehouse Station, NJ 08889-0100 USA reported significant inhibition of hERG by cyanopyrimidine 15, which was attributed to the relatively high basicity (15: pK a 9.2) and lipophilicity (15: clogP 4) of this class of compounds [65]. Ensuing attenuation of the basicity and lipophilicity furnished inhibitors with improved selectivity over hERG, for example, 42 (Cat K IC 50 3 nM, hERG K i 3.2 µM, pK a 7.4, clogP 1.8) [117].…”

Section: Expert Opinionmentioning

confidence: 97%

Inhibitors of cathepsin K: a patent review (2004 – 2010)

Wijkmans

Gossen

2011

Expert Opinion on Therapeutic Patents

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Between 2004 and 2010, more than 50 patent applications have appeared, underlining the continued interest in small molecule cathepsin K inhibition for therapeutic intervention. Most compounds claimed are peptide-derived inhibitors displaying a reversible binding nitrile or ketone warhead. The success of these compounds in the clinic will be determined by the selectivity that can be achieved against other off-target cathepsin. In this respect, eliminating lysosomotropic characteristics may prove to be crucial in the design of selective cathepsin K inhibitors. During the review period, ONO-5334 and odanacatib have progressed to Phase II and Phase III clinical trials, respectively. The results of these studies are eagerly awaited and may determine the future of these agents as disease-modifying therapeutics.

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“…(3) In order to analyze the effect of the molecules on hERG target, a pharmacophore query was generated with the inhibitor present in pdb 3O0U (pharmacophore-5). 29…”

Section: Virtual Screening (Pharmacophore Based)mentioning

confidence: 99%

Binding mode prediction and identification of new lead compounds from natural products as renin and angiotensin converting enzyme inhibitors

et al. 2014

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Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: Improving selectivity over hERG

Cited by 8 publications

References 19 publications

MD-Based Assessment of Covalent Inhibitors in Noncovalent Association Complexes: Learning from Cathepsin K as a Test Case

MD-Based Assessment of Covalent Inhibitors in Noncovalent Association Complexes: Learning from Cathepsin K as a Test Case

Inhibitors of cathepsin K: a patent review (2004 – 2010)

Binding mode prediction and identification of new lead compounds from natural products as renin and angiotensin converting enzyme inhibitors

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