Could the “Janus‐like” properties of the halobenzene CX bond (XCl, Br) be leveraged to enhance molecular recognition?

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, CF 3 , and NHCH 3 , 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. © 2014 Wiley Periodicals, Inc.