Halogen–Aromatic π Interactions Modulate Inhibitor Residence Times

Abstract

Prolonged drug residence times may result in longer-lasting drug efficacy, improved pharmacodynamic properties, and "kinetic selectivity" over off-targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active-state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen-aromatic π interactions in the haspin-inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding-energy calculations.

A structure–kinetic relationship study using matched molecular pair analysis

“…The kinetic dataset KIND (KINetic Dataset) contains a total of 3812 structures and their kinetic data triplets (k on , k off , K D ). It has been compiled from 21 publications 16,19,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] and the K4DD database (for details see the ESI, † the dataset is provided in KIND.xlsx). For the literature search, only papers containing numerical values for all three parameters investigated (K D , k on and k off ) were selected.…”

A promiscuous kinase inhibitor delineates the conspicuous structural features of protein kinase CK2a1

“…The I atom of 5IOD faces the gatekeeper residue in all 5IOD complexes. The higher inhibitory activities of 5IOD for haspin and CLK1 are likely to be attributable to the halogeninteraction between the gatekeeper phenylalanine residue and the I atom (Heroven et al, 2018). Although the gatekeeper residue of CK2a1 is Phe113, as found in haspin and CLK1, this residue is distal from the I atom.…”

“…The reduced interaction of the ribose and I atom of 5IOD with CK2a1 is most likely to account for the lower inhibitory activity of CK2a1 (Table 3). The values for the inhibitory activity and/or the binding dissociation constant extracted from previous reports (Massillon et al, 1994;Kinoshita et al, 2008;Balzano et al, 2011;Heroven et al, 2018) are associated with the number of electrostatic interactions involving hydrogen bonds and halogen-aromatic interactions (Table 3).…”

Influence of Fluorine Substitution on Nonbonding Interactions in Selected Para‐Halogeno Anilines

“…[3,[18][19][20] Organic halides not only endow a molecule with better pharmacokinetic properties, such as increased lipophilicity or metabolic stability of the bioactive agent [7] but also improve the affinity of a drug and its residence time within the binding site of a target protein. [19][20][21] In contrast to heavier halogens (Cl, Br or I), fluorine is not a typical XB donor and HB acceptor. [22][23][24][25][26] However, due to having the highest electronegativity among halogens, the introduction of a fluorine substituent in organic compounds leads to significant changes in the physicochemical properties, reactivity, and biological activity of the new compound compared to its nonfluorinated analog.…”