title: PRO_SELECT: combining structure-based drug design and array-based chemistry for rapid lead discovery. 2. The development of a series of highly potent and selective factor Xa inhibitors.
abstract: In silico screening of combinatorial libraries prior to synthesis promises to be a valuable aid to lead discovery. PRO_SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa. A small seed template was built upon using three iterations of library design, virtual screening, synthesis, and biological testing. Highly potent molecules with selectivity for factor Xa over other serine proteases were rapidly obtained.
authors.affiliation: Protherics Molecular Design, Beechfield House, Lyme Green Business Park, Macclesfield SK11 0JL, UK. jliebeschuetz@tularik.com
authors.forename: John W
authors.initials: JW
authors.lastname: Liebeschuetz
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Jones
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Morgan
authors.forename: Chris W
authors.initials: CW
authors.lastname: Murray
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rimmer
authors.forename: Jonathan M E
authors.initials: JM
authors.lastname: Roscoe
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Welsh
authors.forename: William A
authors.initials: WA
authors.lastname: Wylie
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Young
authors.forename: Harry
authors.initials: H
authors.lastname: Martin
authors.forename: Jacqui
authors.initials: J
authors.lastname: Mahler
authors.forename: Leo
authors.initials: L
authors.lastname: Brady
authors.forename: Kay
authors.initials: K
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001550:Benzamidines; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors