Fluorine Bonding — How Does It Work In Protein−Ligand Interactions?

Abstract

Although fluorination of pharmacologically active compounds has long been a common strategy to increase their metabolic stability and membrane permeation, the functionality of protein-ligand interactions involving fluorine atoms (fluorine bonding) was only recently recognized in the chemistry and biology communities. In this study, the geometric characteristics and the energetic behaviors of fluorine bonding were systematically investigated by combining two quite disparate but complementary approaches: X-ray structural analysis and theoretical calculations. We found that the short contacts involving fluorine atoms (generalized fluorine bonding) between proteins and fluorinated ligands are very frequent, and these contacts, compared to those routine hydrogen/halogen bonding, are more similar to sulfur-involved hydrogen bonding observed in proteins. ONIOM-based quantum mechanics/molecular mechanics analysis further revealed that fluorine bonding does play an essential role in protein-ligand binding, albeit the strength of isolated fluorine bonding is quite modest. Furthermore, 14 quantum mechanics (QM) and molecular mechanics (MM) methods were performed to reproduce fluorine bonding energies obtained at the rigorous MP2/aug-cc-pVDZ level of theory, and the results showed that most QM and very few MM methods perform well in the reproducibility; the MPWLYP functional and MMFF94 force field are recommended to study moderate and large fluorine bonding systems, respectively.

Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

“…Fluorine atoms are hydrogen bond acceptors and may interact with cyt bc 1 residues to facilitate a more rapid or longer lasting inhibition. 33 This could also explain the moderate cross-resistance that Tm90-C2B parasites exhibit toward the 5,7-difluoro substituted ELQs; the mutated Y268 residue plays a predicted role in hydrogen bonding within the Q o site of cyt bc 1 . 34 Ultimately, the major obstacle to ELQ-400 development is its limited selectivity for Plasmodium cyt bc 1 .…”

Fluorine–Protein Interactions and 19F NMR Isotropic Chemical Shifts: An Empirical Correlation with Implications for Drug Design

“…Short orthogonal CÀF···C=O (N) contacts (with C=O being the sp 2 carbon of amides and C=N the guanidinium system of arginines), fluorine-nonpolar hydrogen contacts, and hydrogen bonds are among the most commonly encountered fluorine-protein interactions. [7][8][9][10] Studies to date have treated the fluorine atom as a single species. However, results from NMR studies have shown that the isotropic and anisotropic components of the fluorine chemical shift tensor can vary significantly between different fluorine atoms bound to the same carbon type (sp 2 or sp 3 ).…”

Stepwise high-throughput virtual screening of Rho kinase inhibitors from natural product library and potential therapeutics for pulmonary hypertension

“…The phloretin have a high affinity (DG ¼ À15.7 kcal/mol) to Rho, and an intensive nonbonded network was identified at its complex interface with Rho active pocket. Structural examination revealed that a number of hydrogen bonds and hydrophobic interactions (Zhou et al, 2009(Zhou et al, , 2012 are formed with Tyr155 and Lys200 and with some non-polar residues such as Val137, Met153, and Leu205. A similar phenomenon was also observed in the complex system of Rho with baicalein, albeit non-polar chemical forces such as hydrophobic potential and van der Waals packing are more significant for the ligand binding as compared with phloretin.…”