title: Could the "Janus-like" properties of the halobenzene CX bond (X=Cl, Br) be leveraged to enhance molecular recognition?
abstract: The CX bond in halobenzenes (XCl, 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.
authors.affiliation: Chemistry and Biology, Nucleo(s)tides and Immunology for Therapy (CBNIT), UMR 8601 CNRS, UFR Biomédicale, Paris, France; Centre d'Analyses et de Recherche, UR EGFEM, LSIM, Faculté des Sciences, Saint Joseph University of Beirut, B.P. 11-514 Riad El Solh, Beirut, 1107 2050, Lebanon.
authors.forename: Krystel
authors.initials: K
authors.lastname: El Hage
authors.forename: Jean-Philip
authors.initials: JP
authors.lastname: Piquemal
authors.forename: Zeina
authors.initials: Z
authors.lastname: Hobaika
authors.forename: Richard G
authors.initials: RG
authors.lastname: Maroun
authors.forename: Nohad
authors.initials: N
authors.lastname: Gresh
keywords: anticooperativity; cooperativity; electron-donating substituents; electron-withdrawing substituents; halobenzyl ring; protein-ligand interactions; quantum chemistry; rational drug design; sigma-hole