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.
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.
Liebeschuetz
John W
JW
Protherics Molecular Design, Beechfield House, Lyme Green Business Park, Macclesfield SK11 0JL, UK. jliebeschuetz@tularik.com
Jones
Stuart D
SD
Morgan
Phillip J
PJ
Murray
Chris W
CW
Rimmer
Andrew D
AD
Roscoe
Jonathan M E
JM
Waszkowycz
Bohdan
B
Welsh
Pauline M
PM
Wylie
William A
WA
Young
Stephen C
SC
Martin
Harry
H
Mahler
Jacqui
J
Brady
Leo
L
Wilkinson
Kay
K
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
D001550:Benzamidines; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors