Differentiating Serine and Cysteine Protease Mechanisms by New Covalent QSAR Descriptors

Shokhen, Michael; Traube, Tamar; Vijayakumar, S.; Hirsch, Michal; Uritsky, Neta; Albeck, Amnon

doi:10.1002/cbic.201000459

Cited by 16 publications

(28 citation statements)

References 22 publications

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“…This is further supported by our previous theoretical studies of thiolate reactivity towards different electrophiles,30 and the conclusions derived from experimental kinetic studies of papain 31. We also demonstrated that with a weak Cys nucleophile in Cathepsin K, the binding trend of CS of RCA inhibitors is dominated by the change in pK a of the oxygen atom in TC(OH), which is accounted for by the covalent descriptor W2 13. The QSAR models presented in this work are generated for reversible covalent ketoamide inhibitors of cathepsin K (Figure 10).…”

Section: Resultssupporting

confidence: 84%

“…13), the W2 index accounts for two energetic effects – formation of the enzyme-inhibitor covalent bond and PA/pK a of TC(OH). The latter effect dominates the biding trend of RCA inhibitors with a weak Cys nucleophile 13. Therefore, W2 plays an exclusive role in the QSAR models of cysteine proteases.…”

Section: Resultsmentioning

confidence: 99%

“…The physical background and detailed analysis of the different role of W1 and W2 descriptors in the QSAR models of Ser and Cys nucleophiles is presented in Ref. 13 (see also SI).…”

Section: Resultsmentioning

confidence: 99%

“…The method uses series of isoselective RCA inhibitors, the relative binding affinities of which depend on the variation of their CS fragments only. The binding affinity trend is predicted on small molecular clusters representing the enzyme-inhibitor reaction core in the active site 12,13. The clusters are composed from the functional groups simulating the enzyme nucleophile (Nuc) and the CS fragment of the inhibitor (Inh) (Fig.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

Traube

Vijayakumar

Hirsch

et al. 2010

J. Chem. Inf. Model.

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We introduce an enzyme mechanism-based method, EMBM, aimed at rational design of chemical sites, CS, of reaction coordinate analog inhibitors. The energy of valence reorganization of CS, caused by the formation of the enzyme-inhibitor covalent complex, is accounted for by new covalent descriptors W1 and W2. We considered CS fragments with a carbonyl reactivity center, like in native protease substrates. The W1 and W2 descriptors are calculated quantum mechanically on small molecular clusters simulating the reaction core of the formed covalent tetrahedral complex -anionic TC(O−) or neutral TC(OH). The modeling on a reaction core allows generation of various CS and corresponding TC(O−) and TC(OH) as universal building blocks of real inhibitors and their covalent complexes with serine or cysteine hydrolases. Moreover, the approach avoids the need for 3D structure of the target enzyme, so EMBM may be used for ligand-based design. We have built a Chemical Site of Inhibitors (CSI) databank with pairs of W1 and W2 descriptors pre-calculated for both CH 3 O(−) and CH 3 S(−) nucleophiles for every collected CS fragment. We demonstrated that contribution of a CS fragment to the binding affinity of an inhibitor depends on both its covalent reorganization during the chemical transformation and its non-covalent interactions in the enzyme active site. Consequently, prediction of inhibitors binding trend can be done only by accounting for all of these factors, using W1 and W2 in combination with non-covalent QSAR descriptors.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

“…The physical background and detailed analysis of the different role of W1 and W2 descriptors in the QSAR models of Ser and Cys nucleophiles is presented in Ref. 13 (see also SI).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

Traube

Vijayakumar

Hirsch

et al. 2010

J. Chem. Inf. Model.

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View full text Add to dashboard Cite

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“…We have recently introduced two types of QSAR descriptors, W1 and W2. [18] They quantitatively account for the en- Abstract: Most CADD tools handle non-covalent enzyme inhibitors, despite the growing interest of the pharma industry in covalent inhibitors. We have recently introduced an enzyme mechanism-based method, EMBM, as a computational tool for binding trend analysis and prediction of chemical sites (CS) of reversible covalent enzyme inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Application of EMBM to Structure‐Based Design of Warheads for Protease Inhibitors

Traube

Shokhen

Albeck

2013

Molecular Informatics

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Most CADD tools handle non-covalent enzyme inhibitors, despite the growing interest of the pharma industry in covalent inhibitors. We have recently introduced an enzyme mechanism-based method, EMBM, as a computational tool for binding trend analysis and prediction of chemical sites (CS) of reversible covalent enzyme inhibitors. In the current study we demonstrate the utility of EMBM to structure-based applications. In this mode, the energy of the enzyme-inhibitor covalent bond is accounted for by the W1 and W2 covalent descriptors we have developed, whereas the non-covalent interactions between the inhibitor CS and the enzyme active site can be estimated directly on the 3D structure of the enzyme-inhibitor complex.

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From Catalytic Mechanism to Rational Design of Reversible Covalent Inhibitors of Serine and Cysteine Hydrolases

Shokhen

Hirsch

Khazanov

et al. 2014

Israel Journal of Chemistry

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Mechanistic studies of catalysis and the inhibition of serine and cysteine proteases afford new and sometimes surprising insights, challenging conventional dogmas in enzymology. The intrinsic source of the difference in the catalytic mechanisms of serine and cysteine hydrolases, the origin of the stability of the enzymeinhibitor complex in serine proteases, and the structures and mechanisms of catalysis and inhibition in cysteine proteases are not just intellectually interesting; our findings provide a mechanistic basis to understand the trend in the binding affinity of “warheads” of reversible covalent (reaction coordinate analogue, RCA) inhibitors. The theoretically derived covalent descriptors W1 and W2 differentiate serine and cysteine hydrolases and account for the energetic contribution of the new covalent bond in the enzymeinhibitor complex. The W1 and W2 descriptors are at the heart of our enzyme mechanism based method (EMBM); a new computer‐assisted drug design tool for the filtration of inhibitor warheads by activity. EMBM is unique because it accounts for both covalent and noncovalent interactions of RCA inhibitors with their target enzymes.

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Differentiating Serine and Cysteine Protease Mechanisms by New Covalent QSAR Descriptors

Cited by 16 publications

References 22 publications

EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

Application of EMBM to Structure‐Based Design of Warheads for Protease Inhibitors

From Catalytic Mechanism to Rational Design of Reversible Covalent Inhibitors of Serine and Cysteine Hydrolases

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