title: 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.affiliation: International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, Trieste I-34012, Italy.
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.forename: Thanyarat
authors.initials: T
authors.lastname: Udommaneethanakit
authors.forename: Vladimir
authors.initials: V
authors.lastname: Frecer
authors.forename: Stanislav
authors.initials: S
authors.lastname: Miertus
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001717:Birds; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D053124:Influenza A Virus, H5N1 Subtype / Q000201:enzymology*; D005585:Influenza in Birds / Q000188:drug therapy; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: C456059:A 315675; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D009439:Neuraminidase