Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

Ozeri, Rachel; Khazanov, Netaly; Perlman, Nurit; Shokhen, Michael; Albeck, Amnon

doi:10.1002/cmdc.200600029

Cited by 8 publications

(14 citation statements)

References 39 publications

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“…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%

“…RCA inhibitor can be considered as formally comprised of two parts: the chemical site, CS , responsible for the covalent binding, and the recognition site, RS , dominating in the selectivity of the inhibitor towards the target enzyme 11,12. We have previously introduced a new method that allows a separate design of CS fragments of RCA inhibitors 12.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously introduced a new method that allows a separate design of CS fragments of RCA inhibitors 12. The method uses series of isoselective RCA inhibitors (with identical RS and different CS fragments), in which the relative binding affinity depends on their CS fragments only.…”

Section: Introductionmentioning

confidence: 99%

“…The method uses series of isoselective RCA inhibitors (with identical RS and different CS fragments), in which the relative binding affinity depends on their CS fragments only. The method explicitly accounts only for the covalent interactions between the inhibitor CS fragment and the attacking nucleophile of the enzyme 12. Recently we have introduced new improved covalent QSAR descriptors W1 and W2.…”

Section: Introductionmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…[50] Two sets of the general formula RS-X (RS = carbobenzyloxy (Cbz)-Phe; X = OH, H, CH 3 , COCH 3 , CF 3 and RS = Cbz-Gly-Leu-Phe; X = OH, H, CH 3 , COCH 3 ) were examined with three serine proteases: chymotrypsin, subtilisin, and carboxypeptidase Y. Therefore, noncovalent enzymeÀRS interactions are different for different enzymes of the same family.…”

Section: Serine Protease Inhibition By Rca Inhibitorsmentioning

confidence: 99%

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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The Cooperative Effect Between Active Site Ionized Groups and Water Desolvation Controls the Alteration of Acid/Base Catalysis in Serine Proteases

2007

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What is the driving force that alters the catalytic function of His57 in serine proteases between general base and general acid in each step along the enzymatic reaction? The stable tetrahedral complexes (TC) of chymotrypsin with trifluoromethyl ketone transition state analogue inhibitors are topologically similar to the catalytic transition state. Therefore, they can serve as a good model to study the enzyme catalytic reaction. We used DFT quantum mechanical calculations to analyze the effect of solvation and of polar factors in the active site of chymotrypsin on the pKa of the catalytic histidine in FE (the free enzyme), EI (the noncovalent enzyme inhibitor complex), and TC. We demonstrated that the acid/base alteration is controlled by the charged groups in the active site--the catalytic Asp102 carboxylate and the oxyanion. The effect of these groups on the catalytic His is modulated by water solvation of the active site.

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Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

Cited by 8 publications

References 39 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

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

The Cooperative Effect Between Active Site Ionized Groups and Water Desolvation Controls the Alteration of Acid/Base Catalysis in Serine Proteases

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