Templates for design of inhibitors for serine proteases: Application of the program dock to the discovery of novel inhibitors for thrombin

Scoring ligand similarity in structure‐based virtual screening

“…In this study, 5 of the 26 soluble ligand candidates tested for binding proved to be inhibitors of human thrombin. This success rate is similar to those achieved by other groups, which typically also employ some post-scoring filtering (Shoichet et al, 1993;Massova et al, 1998;Fox and Haaksma, 2000;Schapira et al, 2000Schapira et al, , 2001Doman et al, 2002;Gruneberg et al, 2002;Mizutani and Itai, 2004;Polgar et al, 2005;Zhou et al, 2006). For comparison, experimental high-throughput screening without structure or ligand-based screening typically has a hit rate of less than 1% (Doman et al, 2002;Polgar et al, 2005;Marx et al, 2006;Schepetkin et al, 2006).…”

“…Increases in efficiency and reliability of computational tools have enabled virtual screening to become a routine method in pharmaceutical drug discovery, complementing in vitro highthroughput screening (Schneider and Bohm, 2002;Shoichet et al, 2002;Waszkowycz, 2002;Jorgensen, 2004). Inhibitors have been identified by computational screening of compound databases for protein tyrosine phosphatase-1B (Doman et al, 2002), nuclear hormone receptors (Schapira et al, 2000(Schapira et al, , 2001, human carbonic anhydrase (Gruneberg et al, 2002), thymidylate synthase (Shoichet et al, 1993), integrin alphavbeta3 (Zhou et al, 2006), acetylcholinesterase (Mizutani and Itai, 2004), glycogen synthase kinase-3beta (Polgar et al, 2005), and thrombin (Massova et al, 1998;Bohm et al, 1999;Fox and Haaksma, 2000;Howard et al, 2006). Typically, structure-based virtual screening (in which ligand candidates are docked into the atomic structure of a protein's binding site and evaluated by the resulting protein interactions) and ligand-based screening (in which ligand (www.interscience.wiley.com) DOI:10.1002/jmr.942 candidates are aligned and scored for similarity to a prototypical known ligand) are used independently (Oprea and Matter, 2004;McGaughey et al, 2007).…”

“…A similar approach was used to identify and link small fragments of micromolar potency to create nanomolar inhibitors for thrombin (Howard et al, 2006). DOCK has also been used to screen the CSD for new inhibitors for thrombin (Massova et al, 1998). Three of their top-scoring compounds were found to be competitive inhibitors of thrombin with K i values in the range of 170-1700 mM.…”

Prediction of Non‐bonded Interactions in Drug Design

“…The program DOCK, one of the most widely used docking programs, has been applied in many published studies [73][74][75][76][77][78]. Usually, the DOCK AMBER force field score is applied.…”

Modifications of the scoring function in FlexX for virtual screening applications

“…While the reproduction of experimentally solved complex structures is an accepted way of testing and comparing docking programs [51,52], surprisingly few virtual screening applications have been published. Compound selection based on docking calculations, for example, has been done for thrombin [53,54], thymidylate synthase [55,56], DHFR enzymes [57] and HIV protease [58,59]. However, only in rare cases [13], such studies are conclusive as to the efficiency of the docking tools in enriching subsets of a database in active compounds.…”