Atomistic insights into the inhibition of cysteine proteases: first QM/MM calculations clarifying the stereoselectivity of epoxide-based inhibitors

The Journal of Physical Chemistry. B
Milena MladenovicBernd Engels

Abstract

Due to their important role in many diseases, cysteine proteases represent new promising drug targets. An important class of cysteine-protease inhibitors is derived from the naturally occurring compound E64, possessing an epoxysuccinyl moiety as warhead. Experimental studies show stereoselectivity concerning the inhibition potency, e.g., a trans-configured epoxide ring is essential for inhibition, and furthermore, in most cases, the ( S, S)-configured inhibitors have a higher inhibition potency than their ( R, R)-counterparts. However, the underlying effects are not fully understood. In this work, such effects are investigated by classical molecular dynamics simulations and combined quantum mechanics/molecular modeling (QM/MM) calculations for the E64c-cathepsin B complex. Our computations reveal that the hydrogen bonding network between the enzyme and the E64c (or its derivatives) determines the stereoselectivity of the subsequent ring opening reaction by governing the distance between the attacking thiolate and the attacked C2 atom of the epoxide ring. For the ( S, S)-configuration, a strong network can be realized which enables a close contact between the reacting centers, so that the irreversible step becomes very efficient...Continue Reading

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Citations

Jul 10, 2013·Journal of Medicinal Chemistry·Isaac T SchieferGregory R J Thatcher
Mar 24, 2010·Chemical Communications : Chem Comm·Richard LonsdaleAdrian J Mulholland
Jul 30, 2011·Journal of Molecular Graphics & Modelling·Zhigang ZhouStephen H Bryant
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Sep 14, 2018·Physical Chemistry Chemical Physics : PCCP·Alberto Monteiro Dos SantosCarlos A Montanari
Mar 27, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Philipp KleinTanja Schirmeister
Sep 25, 2014·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Thomas C SchmidtBernd Engels
May 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Philipp KleinTanja Schirmeister
Mar 4, 2020·Journal of Chemical Information and Modeling·José Rogério A SilvaCarlos A Montanari
Apr 4, 2021·International Journal of Molecular Sciences·Brigitta Elsässer, Peter Goettig
Mar 24, 2009·The Journal of Physical Chemistry. B·Verena BubackTanja Schirmeister
Sep 2, 2009·The Journal of Organic Chemistry·Alexander PaascheBernd Engels
Jan 17, 2013·The Journal of Physical Chemistry. B·Rong-Zhen Liao, Walter Thiel
Jan 17, 2020·Journal of Chemical Information and Modeling·Clauber H S da CostaCarlos A Montanari

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