Structure-Based Characterization and Optimization of Novel Hydrophobic Binding Interactions in a Series of Pyrrolidine Influenza Neuraminidase Inhibitors

Abstract

The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.

Multiple field three dimensional quantitative structure–activity relationship (MF‐3D‐QSAR)

“…Total 32 molecule samples are used in the training set. The molecular structures and bioactivities pIC 50 of the 32 molecules 24 are listed in Table1. According to the standard 3D-QSAR methods, such as CoMFA and CoMSIA, a cubic grid is set up surrounding the aligned ligand molecules and thousands upon thousands potential values at these grid points are calculated.…”

QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR

“…In total, 126 known NIs were prepared in this study, and their bioactivities against influenza A virus were mainly taken from the literature [12,16,[22][23][24][25][26] ( Table 1). IC 50 values are available for most inhibitors except for a series of pyrrolidine NIs [12], for which IC 50 values were calculated from K i values using the Cheng-Prusoff equation [27].…”

“…Rational drug design utilizing available X-ray crystal structures of NA-inhibitor complexes has led to the discovery of some six-membered ring NIs including those two marketed drugs mentioned above [9,10]. Recently, a series of pyrrolidine and cyclopentane-based NIs were also developed by employing an iterative structurebased methods [12,13], some of which have shown equal or better efficacies on comparison with oseltamivir carboxylate and zanamivir [14]. Correlating the physicochemical properties of compounds or the computed binding energies with inhibitory activities is believed to gain an insight into the interaction mechanism of NA to inhibitors, and recently Verma et al reported 17 quantitative structure-activity relationships (QSAR) for different sets of NIs [15].…”

“…Besides, this model contains few or no oseltamivir analogues (in fact, only the GS4071 was included but with an incorrect scaffold as depicted), which shows both clinical and pharmacological perspective on NA H5N1 influenza treatment [18]. In recent years, novel NIs kept emerging, with both different inhibitory profiles and chemically more accessible scaffolds [12,19]. Thereby, it is high time to construct new QSAR models to get further insight into the relationship between molecular structures and bioactivities, in order to provide guidelines for the development of potent NIs with novel structures.…”

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

“…Whereas oseltamivir can be described as a cyclohexenyl derivative, there are a number of cyclopentane and pyrrolidine derivatives that have been described as neuraminidase inhibitors: peramivir (RWJ -270201, BCX -1182) 67 -69 and other cyclopentane 69,70 and cyclopentane amide 71 derivatives as well as a variety of pyrrolidine derivatives, including A -192558, 72 A -315675, 73 -75 and other pyrrolidines 76 (Fig. 1.8 ).…”