A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.

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Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

he impact of influenza infection is felt globally each year when the disease develops in approximately 20 percent of the world’s population. In the United States, influenza infections occur in epidemics each winter, generally between late December and early March. Recent events, including human cases of avian influenza, have heightened awareness of the threat of a pandemic and have spurred efforts to develop plans for its control. Although vaccination is the primary strategy for the prevention of influenza, there are a number of likely scenarios for which vaccination is inadequate and effective antiviral agents would be of the utmost importance. During any influenza season, antigenic drift in the virus may occur after formulation of the year’s vaccine has taken place, rendering the vaccine less protective, and outbreaks can more easily occur among highrisk populations. In the course of a pandemic, vaccine supplies would be inadequate. Vaccine production by current methods cannot be carried out with the speed required to halt the progress of a new strain of influenza virus; therefore, it is likely that vaccine would not be available for the first wave of spread of virus. 1 Antiviral agents thus form an important part of a rational approach to epidemic influenza and are critical to planning for a pandemic. Four drugs are currently available for the treatment or prophylaxis of influenza infections: the adamantanes (amantadine and rimantadine) and the newer class of neuraminidase inhibitors (zanamivir [Relenza] and oseltamivir [Tamiflu]). The adamantanes interfere with viral uncoating inside the cell. They are effective only against influenza A and are associated with several toxic effects and with rapid emergence of drug-resistant variants. Adamantane-resistant isolates of influenza A are genetically stable, can be transmitted to susceptible contacts, are as pathogenic as wild-type virus isolates, and can be shed for prolonged periods in immunocompromised patients taking the drug. This potential for the development of resistance especially limits the use of the adamantanes for the treatment of influenza, although the drugs still have a place in planning for prophylaxis during an epidemic. The neuraminidase inhibitors zanamivir and oseltamivir interfere with the release of progeny influenza virus from infected host cells, a process that prevents infection of new host cells and thereby halts the spread of infection in the respiratory tract (Fig. 1). Since replication of influenza virus in the respiratory tract reaches its peak between 24 and 72 hours after the onset of the illness, drugs such as the neuraminidase inhibitors that act at the stage of viral replication must be administered as early as possible. In contrast to the adamantanes, the neuraminidase inhibitors are associated with very little toxicity and are far less likely to promote the development of drug-resistant influenza. As a class, the neuraminidase inhibitors are effective against all neuraminidase subtypes t

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Neuraminidase Inhibitors for Influenza

ContextPrevious studies have shown oseltamivir, a neuraminidase inhibitor,
to be effective in preventing influenza and treating experimental influenza.ObjectiveTo evaluate the efficacy and safety of oseltamivir in the treatment
of naturally acquired influenza infection.DesignRandomized, placebo-controlled, double-blind study conducted January
through March 1998.SettingSixty primary care and university health centers throughout the United
States.ParticipantsA total of 629 healthy nonimmunized adults aged 18 to 65 years with
febrile respiratory illness of no more than 36 hours' duration with temperature
of 38°C or more plus at least 1 respiratory symptom and 1 constitutional
symptom.InterventionsIndividuals were randomized to 1 of 3 treatment groups with identical
appearing pills: oral oseltamivir phosphate, 75 mg twice daily (n = 211) or
150 mg (n = 209) twice daily, or placebo (n = 209).Main Outcome MeasuresDuration and severity of illness in individuals infected with influenza.ResultsTwo individuals withdrew before receiving medication and were excluded
from further analyses. A total of 374 individuals (59.6%) were infected with
influenza. Their duration of illness was reduced by more than 30% with both
oseltamivir, 75 mg twice daily (median, 71.5 hours; P<.001),
and oseltamivir, 150 mg twice daily (median, 69.9 hours; P = .006), compared with placebo (median, 103.3 hours). Severity of
illness was reduced by 38% (median score, 597 score-hours; P<.001) with oseltamivir, 75 mg twice daily, and by 35% (median
score, 626 score-hours; P<.001) with oseltamivir,
150 mg twice daily, vs placebo (median score, 963 score-hours). Oseltamivir
treatment reduced the duration of fever and oseltamivir recipients returned
to usual activities 2 to 3 days earlier than placebo recipients (P≤.05). Secondary complications such as bronchitis and sinusitis
occurred in 15% of placebo recipients compared with 7% of combined oseltamivir
recipients (P = .03). Among all 629 subjects, oseltamivir
reduced illness duration (76.3 hours and 74.3 hours for 75 mg and 150 mg,
respectively, vs 97.0 hours for placebo; P = .004
for both comparisons) and illness severity (686 score-hours and 629 score-hours
for 75 mg and 150 mg, respectively, vs 887 score-hours for placebo; P<.001 for both comparisons). Nausea and vomiting occurred
more frequently in both oseltamivir groups (combined, 18.0% and 14.1%, respectively; P = .002) than in the placebo group (7.4% and 3.4%; P<.001).ConclusionsOur data suggest that oral oseltamivir treatment reduces the duration
and severity of acute influenza in healthy adults and may decrease the incidence
of secondary complications.

https://jamanetwork.com/journals/jama/articlepdf/192425/JOC91318.pdf

Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza

Multicomponent reactions: advanced tools for sustainable organic synthesis

The design, synthesis, and in vitro evaluation of the novel carbocycles as transition-state-based inhibitors of influenza neuraminidase (NA) are described. The double bond position in the carbocyclic analogues plays an important role in NA inhibition as demonstrated by the antiviral activity of 8 (IC50 = 6.3 μM) vs 9 (IC50 > 200 μM). Structure−activity studies of a series of carbocyclic analogues 6a−i identified the 3-pentyloxy moiety as an apparent optimal group at the C3 position with an IC50 value of 1 nM for NA inhibition. The X-ray crystallographic structure of 6h bound to NA revealed the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid. The high antiviral potency observed for 6h appears to be attributed to a highly favorable hydrophobic interaction in this pocket. The practical synthesis of 6 starting from (−)-quinic acid is also described.

Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity.

A series of influenza neuraminidase inhibitors with the cyclohexene scaffold containing lipophilic side chains have been synthesized and evaluated for influenza A and B neuraminidase inhibitory activity. The size and geometry of side chains have been modified systematically in order to investigate structure-activity relationships of this class of compounds. The X-ray crystal structures of several analogues complexed with neuraminidase revealed that the lipophilic side chains bound to the hydrophobic pocket consisted of Glu276, Ala246, Arg224, and Ile222 of the enzyme active site. The structure-activity relationship studies of this series have also demonstrated remarkably different inhibitory potency between influenza A and B neuraminidase. This indicated that the lipophilic side chains had quite different hydrophobic interactions with influenza A and B neuraminidase despite their complete homology in the active site. Influenza B neuraminidase appeared to be much more sensitive toward the increased steric bulkiness of inhibitors compared to influenza A neuraminidase. From the extensive structure-activity relationship investigation reported in this article, GS 4071 emerged as one of the most potent influenza neuraminidase inhibitors against both influenza A and B strains.

Structure−Activity Relationship Studies of Novel Carbocyclic Influenza Neuraminidase Inhibitors

The discovery of (+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N'-ethyl-N'-isopropylcarbamyl)pyrrolidine-4-carboxylic acid (A-192558, 20e) as a potent inhibitor of influenza neuraminidase (NA) is described. Efficient syntheses of two core structures, cis-3-(allyloxycarbonyl)amino-1-(9'-fluorenylmethoxycarbonyl)pyrrolidine-4-carboxylic acid (7) and tert-butyl (+/-)-(2S,3R,4R)-2-aminomethyl-3-bis(tert-butyloxycarbonyl)amino-1-(N'-ethyl-N'-isopropylcarbamyl)pyrrolidine-4-carboxylate (18b), were developed. Starting with these core structures and using available structural information of the NA active site as the guide, analogues were synthesized in both the tri- and tetrasubstituted pyrrolidine series by means of high-throughput parallel synthesis in solid or solution phase for expeditious SAR. These studies accelerated the identification of (+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N-ethyl-N-isopropylcarbamyl)pyrrolidine-4-carboxylate (20e, A-192558) as the most potent NA inhibitor in this series (IC50 = 0.2 microM against NA A and 8 microM against NA B). The X-ray crystallographic structure of A-192558 bound to NA revealed the predicted interaction of the carboxylic group with the positively charged pocket (Arg118, Arg292, Arg371) and interaction of the trifluoroacetamino residue with the hydrophobic pocket (Ile222, Trp178) of the enzyme active site. Surprisingly, the ethyl and isopropyl groups of the urea functionality induced a conformational change of Glu276, turning the Glu276/Glu277 hydrophilic pocket, which normally accommodates the triglycerol side chain of substrate sialic acid, into an induced hydrophobic pocket.

Design, synthesis, and structural analysis of influenza neuraminidase inhibitors containing pyrrolidine cores.

Influenza Neuraminidase Inhibitors Possessing a Novel Hydrophobic Interaction in the Enzyme Active Site: Design, Synthesis, and Structural Analysis of Carbocyclic Sialic Acid Analogues with Potent Antiinfluenza Activity.

W. G. Laver

Papers

Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity.

Structure−Activity Relationship Studies of Novel Carbocyclic Influenza Neuraminidase Inhibitors

Design, synthesis, and structural analysis of influenza neuraminidase inhibitors containing pyrrolidine cores.

Influenza Neuraminidase Inhibitors Possessing a Novel Hydrophobic Interaction in the Enzyme Active Site: Design, Synthesis, and Structural Analysis of Carbocyclic Sialic Acid Analogues with Potent Antiinfluenza Activity.

58 Design, synthesis and activity of substituted pyrrolidine influenza neuraminidase inhibitors