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231224s2015 xx |||||o 00| ||eng c |
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|a 10.1002/jcc.23786
|2 doi
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|a pubmed24n0812.xml
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|a (DE-627)NLM243644515
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|a (NLM)25408206
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|a DE-627
|b ger
|c DE-627
|e rakwb
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|a eng
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|a El Hage, Krystel
|e verfasserin
|4 aut
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|a Could the "Janus-like" properties of the halobenzene CX bond (X=Cl, Br) be leveraged to enhance molecular recognition?
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|c 2015
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|a Text
|b txt
|2 rdacontent
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|a ƒaComputermedien
|b c
|2 rdamedia
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|a ƒa Online-Ressource
|b cr
|2 rdacarrier
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|a Date Completed 31.07.2015
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|a Date Revised 02.02.2015
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|a published: Print-Electronic
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|a Citation Status PubMed-not-MEDLINE
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|a © 2014 Wiley Periodicals, Inc.
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|a The CX bond in halobenzenes (XCl, Br) exhibits a dual character, being electron-deficient along the CX direction, and electron-rich on its flanks. We sought to amplify both features by resorting to electron-withdrawing and electron-donating substituents, respectively. This was done by quantum chemistry (QC) computations in the recognition sites of three protein targets: farnesyl transferase, coagulation factor Xa, and the HIV-1 integrase. In this context, some substituents, notably fluorine, CF3 , and NHCH3 , afforded significant overall gains in the binding energies as compared to the parent halobenzene, in the 2-5 kcal/mol range. In fact, we found that some di- and up to tetra-substitutions enabled even larger gains than those they contribute separately owing to many-body effects. Moreover, desolvation was also found to be a key contributor to the energy balances. As a consequence, some particular substituents, contributing to reduce the halobenzene dipole moment, accordingly reduced solvation: this factor acted in synergy with their enhancement of the intermolecular interaction energies along and around the CX bond. We could thus leverage the "Janus-like" properties of such a bond and the fact that it can be tuned and possibly amplified by well-chosen substituents. We propose a simple yet rigorous computational strategy resorting to QC to prescreen novel substituted halobenzenes. The QC results on the recognition sites then set benchmarks to validate polarizable molecular mechanics/dynamics approaches used to handle the entirety of the inhibitor-protein complex
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|a Journal Article
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|a anticooperativity
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|a cooperativity
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|a electron-donating substituents
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|a electron-withdrawing substituents
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|a halobenzyl ring
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|a protein-ligand interactions
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|a quantum chemistry
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|a rational drug design
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|a sigma-hole
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|a Piquemal, Jean-Philip
|e verfasserin
|4 aut
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|a Hobaika, Zeina
|e verfasserin
|4 aut
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| 700 |
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|a Maroun, Richard G
|e verfasserin
|4 aut
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| 700 |
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|a Gresh, Nohad
|e verfasserin
|4 aut
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| 773 |
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|i Enthalten in
|t Journal of computational chemistry
|d 1984
|g 36(2015), 4 vom: 05. Feb., Seite 210-21
|w (DE-627)NLM098138448
|x 1096-987X
|7 nnns
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| 773 |
1 |
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|g volume:36
|g year:2015
|g number:4
|g day:05
|g month:02
|g pages:210-21
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|u http://dx.doi.org/10.1002/jcc.23786
|3 Volltext
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