Combinatorial design of avian influenza neuraminidase inhibitors containing pyrrolidine core with a reduced susceptibility to viral drug resistance.

Abstract

Using computer-assisted combinatorial chemistry techniques, we have designed a virtual library of anti-influenza agents, analogs of inhibitor A-315675, containing a novel pyrrolidine core, which effectively inhibits both wild type and common oseltamivir-resistant mutant forms of the neuraminidase (NA) subtype N1 of avian influenza virus H5N1. A target-specific Potential of Mean Force (PMF) scoring function parameterized on a training set of 13 known pyrrolidine-based inhibitors of NA and validated on 3 others was used to predict the N1 inhibition constants for the focused library of A-315675 analogs. Nine virtual hits (best pyrrolidine inhibitors designed in the present study) are predicted to exhibit inhibition constants in the low picomolar range, up to 200 fold lower than the parent inhibitor A-315675 while displaying favorable predicted ADME-related properties. Proposed small highly-focused combinatorial subsets composed of R-groups most frequently occurring in the 200 most active analogs can be useful as a guide for synthetic and medicinal chemists who are developing a new generation of drugs against the avian influenza virus H5N1 by focusing their attention to this small portion of the chemical space.

• Authors: Thanyada Rungrotmongkol, Thanyarat Udommaneethanakit, Vladimir Frecer, Stanislav Miertus
• Journal: Combinatorial chemistry & high throughput screening (Comb Chem High Throughput Screen) Vol. 13 Issue 3 Pg. 268-77 (Mar 2010) ISSN: 1875-5402 [Electronic] United Arab Emirates
• PMID: 20015013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• A 315675
• Antiviral Agents
• Enzyme Inhibitors
• Pyrrolidines
• Neuraminidase

Topics

• Animals
• Antiviral Agents (chemistry, pharmacology)
• Birds
• Combinatorial Chemistry Techniques (methods)
• Computer Simulation
• Drug Design
• Enzyme Inhibitors (chemistry, pharmacology)
• Influenza A Virus, H5N1 Subtype (enzymology)
• Influenza in Birds (drug therapy)
• Models, Molecular
• Neuraminidase (antagonists & inhibitors, metabolism)
• Pyrrolidines (chemistry, pharmacology)
• Quantitative Structure-Activity Relationship