Derivatives of 4-Amino-Pyridine as Selective Thrombin Inhibitors

Saal, Wolfgang von der; Kucznierz, Ralf; Leinert, Herbert; Engh, Richard A.

doi:10.1016/s0960-894x(97)00210-2

Cited by 33 publications

(13 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structures of the 32 thrombin ligands used in this work have been presented in detail in previous studies 50, 51. The coordinates of their ligand‐bound conformations were obtained either from the PDB42 or an unpublished internal database 52, 53. All calculations were performed on a SGI/R10000 machine.…”

Section: Resultsmentioning

confidence: 99%

Similarity-driven flexible ligand docking

Fradera¹,

Knegtel²,

Mestres³

2000

Proteins

View full text Add to dashboard Cite

A similarity‐driven approach to flexible ligand docking is presented. Given a reference ligand or a pharmacophore positioned in the protein active site, the method allows inclusion of a similarity term during docking. Two different algorithms have been implemented, namely, a similarity‐penalized docking (SP‐DOCK) and a similarity‐guided docking (SG‐DOCK). The basic idea is to maximally exploit the structural information about the ligand binding mode present in cases where ligand‐bound protein structures are available, information that is usually ignored in standard docking procedures. SP‐DOCK and SG‐DOCK have been derived as modified versions of the program DOCK 4.0, where the similarity program MIMIC acts as a module for the calculation of similarity indices that correct docking energy scores at certain steps of the calculation. SP‐DOCK applies similarity corrections to the set of ligand orientations at the end of the ligand incremental construction process, penalizing the docking energy and, thus, having only an effect on the relative ordering of the final solutions. SG‐DOCK applies similarity corrections throughout the entire ligand incremental construction process, thus affecting not only the relative ordering of solutions but also actively guiding the ligand docking. The performance of SP‐DOCK and SG‐DOCK for binding mode assessment and molecular database screening is discussed. When applied to a set of 32 thrombin ligands for which crystal structures are available, SG‐DOCK improves the average RMSD by ca. 1 Å when compared with DOCK. When those 32 thrombin ligands are included into a set of 1,000 diverse molecules from the ACD, DIV, and WDI databases, SP‐DOCK significantly improves the retrieval of thrombin ligands within the first 10% of each of the three databases with respect to DOCK, with minimal additional computational cost. In all cases, comparison of SP‐DOCK and SG‐DOCK results with those obtained by DOCK and MIMIC is performed. Proteins 2000;40:623–636. © 2000 Wiley‐Liss, Inc.

show abstract

Section: Resultsmentioning

confidence: 99%

Similarity-driven flexible ligand docking

Fradera¹,

Knegtel²,

Mestres³

2000

Proteins

View full text Add to dashboard Cite

show abstract

“…50,51 The coordinates of their ligand-bound conformations were obtained either from the PDB 42 or an unpublished internal database. 52,53 All calculations were performed on a SGI/ R10000 machine.…”

Section: Resultsmentioning

confidence: 99%

Similarity‐driven flexible ligand docking

Fradera¹,

Knegtel²,

Mestres³

2000

Proteins

View full text Add to dashboard Cite

A similarity-driven approach to flexible ligand docking is presented. Given a reference ligand or a pharmacophore positioned in the protein active site, the method allows inclusion of a similarity term during docking. Two different algorithms have been implemented, namely, a similarity-penalized docking (SP-DOCK) and a similarity-guided docking (SG-DOCK). The basic idea is to maximally exploit the structural information about the ligand binding mode present in cases where ligand-bound protein structures are available, information that is usually ignored in standard docking procedures. SP-DOCK and SG-DOCK have been derived as modified versions of the program DOCK 4.0, where the similarity program MIMIC acts as a module for the calculation of similarity indices that correct docking energy scores at certain steps of the calculation. SP-DOCK applies similarity corrections to the set of ligand orientations at the end of the ligand incremental construction process, penalizing the docking energy and, thus, having only an effect on the relative ordering of the final solutions. SG-DOCK applies similarity corrections throughout the entire ligand incremental construction process, thus affecting not only the relative ordering of solutions but also actively guiding the ligand docking. The performance of SP-DOCK and SG-DOCK for binding mode assessment and molecular database screening is discussed. When applied to a set of 32 thrombin ligands for which crystal structures are available, SG-DOCK improves the average RMSD by ca. 1 A when compared with DOCK. When those 32 thrombin ligands are included into a set of 1,000 diverse molecules from the ACD, DIV, and WDI databases, SP-DOCK significantly improves the retrieval of thrombin ligands within the first 10% of each of the three databases with respect to DOCK, with minimal additional computational cost. In all cases, comparison of SP-DOCK and SG-DOCK results with those obtained by DOCK and MIMIC is performed.

show abstract

“…However, none of the compounds was pharmacologically characterized From screening Boehringer-Mannheim identified compounds containing a moderately charged C-terminal aminopyridine group (pK a = 9.2 of the aromatic nitrogen). Several analogs, such as 104 (K i = 23 nM) and 105 (K i = 70 nM) are highly selective thrombin inhibitors [145,146] and were optimised further in the course of work (106, K i = 3.2 nM) [147]. The same basic structure was used by 3D Pharmaceuticals, however they replaced the aminopyridine group by an alkyl chain with a terminal amidinohydrazone (pK a = 8.1) or oxyguanidine (pK a = 7.05) group similar as found in canavanine (see 83).…”

Section: Inhibitors Of Other Structural Typementioning

confidence: 99%

Progress in the Development of Synthetic Thrombin Inhibitors as New Orally Active Anticoagulants

Steinmetzer

Stürzebecher²

2004

CMC

View full text Add to dashboard Cite

The trypsin-like serine protease thrombin is a multifunctional key enzyme at the final step of the coagulation cascade and is involved in the regulation of hemostasis and thrombosis. An increased activation of coagulation can result in severe thromboembolic disorders, one of the major reasons responsible for mortality and morbidity in western world. Therefore, an effective, safe, and orally available thrombin inhibitor could be a useful anticoagulant drug for the daily prophylaxis of venous and arterial thrombosis and prevention of myocardial infarction for high-risk patients. Synthetic thrombin inhibitors have a long history; initial compounds were derived from electrophilic ketone- and aldehyde-analogs of arginine. First potent leads of non-covalent inhibitors were developed in the early eighties, which were further optimised in the nineties, after the X-ray structure of thrombin became available. In the meantime a huge number of highly active and selective inhibitors has been published, however, only a few of them have an appropriate pharmacokinetic and pharmacodynamic overall profile, which could justify their further development. Very recently, with Ximelagatran a first orally available thrombin inhibitor has been approved in France for the prevention of venous thromboembolic events in major orthopaedic surgery after successful clinical phase III. However, it still has to be awaited, whether the extensive clinical use of Ximelagatran can demonstrate for the first time that direct thrombin inhibitors offer a real benefit in terms of efficacy and safety over established antithrombotic therapies. This review summarizes the current status of synthetic thrombin inhibitors with a focus on more recently published and promising new compounds.

show abstract

Derivatives of 4-Amino-Pyridine as Selective Thrombin Inhibitors

Cited by 33 publications

References 14 publications

Similarity-driven flexible ligand docking

Similarity-driven flexible ligand docking

Similarity‐driven flexible ligand docking

Progress in the Development of Synthetic Thrombin Inhibitors as New Orally Active Anticoagulants

Contact Info

Product

Resources

About