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Statements

Subject Item
n2:RIV%2F61388963%3A_____%2F13%3A00422118%21RIV14-MSM-61388963
rdf:type
skos:Concept n7:Vysledek
dcterms:description
The quantum mechanics (QM)-based scoring function that we previously developed for the description of noncovalent binding in protein ligand complexes has been modified and extended to treat covalent binding of inhibitory ligands. The enhancements are (i) the description of the covalent bond breakage and formation using hybrid QM/semiempirical QM (QM/SQM) restrained optimizations and (ii) the addition of the new Delta G(cov)' term to the noncovalent score, describing the %22free%22 energy difference between the covalent and noncovalent complexes. This enhanced QM-based scoring function is applied to a series of 20 vinyl sulfone-based inhibitory compounds inactivating the cysteine peptidase cathepsin B1 of the Schistosoma mansoni parasite (SmCB1). The available X-ray structure of the SmCB1 in complex with a potent vinyl sulfone inhibitor K11017 is used as a template to build the other covalently bound complexes and to model the derived noncovalent complexes. We present the correlation of the covalent score and its constituents with the experimental binding data. Four outliers are identified. They contain bulky R-I' substituents structurally divergent from the template, which might induce larger protein rearrangements than could be accurately modeled. In summary, we propose a new computational approach and an optimal protocol for the rapid evaluation and prospective design of covalent inhibitors with a conserved binding mode. The quantum mechanics (QM)-based scoring function that we previously developed for the description of noncovalent binding in protein ligand complexes has been modified and extended to treat covalent binding of inhibitory ligands. The enhancements are (i) the description of the covalent bond breakage and formation using hybrid QM/semiempirical QM (QM/SQM) restrained optimizations and (ii) the addition of the new Delta G(cov)' term to the noncovalent score, describing the %22free%22 energy difference between the covalent and noncovalent complexes. This enhanced QM-based scoring function is applied to a series of 20 vinyl sulfone-based inhibitory compounds inactivating the cysteine peptidase cathepsin B1 of the Schistosoma mansoni parasite (SmCB1). The available X-ray structure of the SmCB1 in complex with a potent vinyl sulfone inhibitor K11017 is used as a template to build the other covalently bound complexes and to model the derived noncovalent complexes. We present the correlation of the covalent score and its constituents with the experimental binding data. Four outliers are identified. They contain bulky R-I' substituents structurally divergent from the template, which might induce larger protein rearrangements than could be accurately modeled. In summary, we propose a new computational approach and an optimal protocol for the rapid evaluation and prospective design of covalent inhibitors with a conserved binding mode.
dcterms:title
Quantum Mechanics-Based Scoring Rationalizes the Irreversible Inactivation of Parasitic Schistosoma mansoni Cysteine Peptidase by Vinyl Sulfone Inhibitors Quantum Mechanics-Based Scoring Rationalizes the Irreversible Inactivation of Parasitic Schistosoma mansoni Cysteine Peptidase by Vinyl Sulfone Inhibitors
skos:prefLabel
Quantum Mechanics-Based Scoring Rationalizes the Irreversible Inactivation of Parasitic Schistosoma mansoni Cysteine Peptidase by Vinyl Sulfone Inhibitors Quantum Mechanics-Based Scoring Rationalizes the Irreversible Inactivation of Parasitic Schistosoma mansoni Cysteine Peptidase by Vinyl Sulfone Inhibitors
skos:notation
RIV/61388963:_____/13:00422118!RIV14-MSM-61388963
n7:predkladatel
n8:ico%3A61388963
n3:aktivita
n11:I n11:P
n3:aktivity
I, P(ED2.1.00/03.0058), P(GA203/09/1585), P(GBP208/12/G016), P(LH12023)
n3:cisloPeriodika
48
n3:dodaniDat
n12:2014
n3:domaciTvurceVysledku
Brahmkshatriya, Pathik n10:1888986 n10:5993768 n10:5796644 n10:8133859 n10:3849147 n10:2932016 n10:9846476
n3:druhVysledku
n15:J
n3:duvernostUdaju
n18:S
n3:entitaPredkladatele
n19:predkladatel
n3:idSjednocenehoVysledku
101231
n3:idVysledku
RIV/61388963:_____/13:00422118
n3:jazykVysledku
n9:eng
n3:klicovaSlova
density-functional theory; protein-ligand; drug design
n3:klicoveSlovo
n14:drug%20design n14:density-functional%20theory n14:protein-ligand
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[9C38ABD5EE88]
n3:nazevZdroje
Journal of Physical Chemistry B
n3:obor
n17:CF
n3:pocetDomacichTvurcuVysledku
8
n3:pocetTvurcuVysledku
8
n3:projekt
n4:GBP208%2F12%2FG016 n4:LH12023 n4:ED2.1.00%2F03.0058 n4:GA203%2F09%2F1585
n3:rokUplatneniVysledku
n12:2013
n3:svazekPeriodika
117
n3:tvurceVysledku
Lepšík, Martin Fanfrlík, Jindřich Hobza, Pavel Mareš, Michael Jílková, Adéla Řezáč, Jan Horn, Martin Brahmkshatriya, Pathik
n3:wos
000328101100010
s:issn
1520-6106
s:numberOfPages
10
n13:doi
10.1021/jp409604n