Influenza Neuraminidase Inhibitors:  Structure-Based Design of a Novel Inhibitor Series

Abstract

Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K(i) = 58 microM via a potency enhancement of >70 000-fold to an analogue with an activity of K(i) = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure-activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180 degrees variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.

Perspective: Alchemical free energy calculations for drug discovery

“…19,70,89 In cases where the ligand binding mode is maintained as functional groups are modified, conventional relative free energy calculations may often work well without any special treatment of alternate potential binding modes. However, small modifications to ligands do on occasion yield big differences in ligand binding orientation, 65,88,[90][91][92][93][94][95][96][97] and there is currently no way to know when this will happen. For example, Stout et al developed a series of thymidylate synthase (TS) inhibitors based on phenolphthalein and phthalein derivatives.…”

“…91 A variety of data suggests this same conclusion may hold true in a variety of other systems. 20,68,88,[97][98][99][100][101][102][103] Going beyond ligand orientation, closely related ligands can bind with significantly different protein conformations. Protein conformational changes can be important, and even protein side chain differences in the binding site can be slow and, calculations indicate, thermodynamically significant.…”

Importance of Neuraminidase Active-Site Residues to the Neuraminidase Inhibitor Resistance of Influenza Viruses

“…The hydrophobic faces of R224, I222, and A246 form a hydrophobic pocket to accommodate the glycerol side chain of sialic acid and zanamivir, while E276 forms a hydrogen bond with the O8 and O9 hydroxyls of the glycerol group (33,34). The interaction of R224 and E276 with oseltamivir is different in that the glycerol side chain is substituted by a pentyl ether group (Table 1).…”

Viral membrane fusion: is glycoprotein G of rhabdoviruses a representative of a new class of viral fusion proteins?

“…Indeed, although most of the antiviral drugs have been developed against viral enzymes involved in virus replication, recent studies have demonstrated that the entry events can also serve as a new target to block viral infection (59,60). As an example, the progress in understanding the mechanisms of HIV-1 cell entry into target cells permitted the design of a new class of anti-HIV-1 drugs: compounds that act as fusion or entry inhibitors that are currently being evaluated in clinical trials (60).…”