64471-88-1Relevant academic research and scientific papers
Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: Synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors
Muley, Laveena,Baum, Bernhard,Smolinski, Michael,Freindorf, Marek,Heine, Andreas,Klebe, Gerhard,Hangauer, David G.
supporting information; experimental part, p. 2126 - 2135 (2010/08/19)
Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per ?2 of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per ?2 demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.
In-depth study of tripeptide-based α-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1′ subsite and its implications to structure-based drug design
Costanzo, Michael J.,Almond Jr., Harold R.,Hecker, Leonard R.,Schott, Mary R.,Yabut, Stephen C.,Zhang, Han-Cheng,Andrade-Gordon, Patricia,Corcoran, Thomas W.,Giardino, Edward C.,Kauffman, Jack A.,Lewis, Joan M.,De Garavilla, Lawrence,Haertlein, Barbara J.,Maryanoff, Bruce E.
, p. 1984 - 2008 (2007/10/03)
Thrombin inhibitors are potentially useful in medicine for their anticoagulant and antithrombotic effects. We synthesized and evaluated diverse heterocycle-activated ketones based on the D-Phe-Pro-Arg, and related thrombin active-site recognition motifs, as candidate inhibitors. The peptide-based α-ketoheterocycles were typically prepared by either an imidate or a Weinreb amide route (Schemes 1 and 2), the latter of which proved to be more general. Test compounds were generally assayed for inhibition of human α-thrombin and bovine trypsin. From a structure-based design standpoint, the heterocycle allows one to explore and adjust interactions within the S1′ subsite of thrombin. The preferred α-ketoheterocycle is a π-rich 2-substituted azole with at least two heteroatoms proximal to the carbon bearing the keto group, and a preferred thrombin inhibitor is 2-ketobenzothiazole 3, with a potent Ki value of 0.2 nM and ca. 15-fold selectivity over trypsin. 2-Ketobenzothiazole 13 exhibited exceedingly potent thrombin inhibition (Ki = 0.000 65 nM; slow tight binding). Several α-ketoheterocycles had thrombin Ki values in the range 0.1-400 nM. The "Arg" unit in the α-ketoheterocycles can be sensitive to stereomutation under mildy basic conditions. For example, 2-ketothiazoles 4 and 59 readily epimerize at pH 7.4, although they are fairly stable stereochemically at pH 3-4; thus, suitable conditions had to be selected for the enzymatic assays. Lead D-Phe-Pro-Arg 2-benzothiazoles 3, 4, and 68 displayed good selectivity for thrombin over other key coagulation enzymes (e.g., factor Xa, plasmin, protein Ca, uPA, tPA, and streptokinase); however, their selectivity for thrombin over trypsin was modest (50 = 30-40 nM). They also proved to be potent anticoagulant/ antithrombotic agents in vivo on intravenous administration, as determined in the canine arteriovenous shunt (ED50 = 0.45-0.65 mg/kg) and the rabbit deep vein thrombosis (ED50 = 0.1-0.4 mg/kg) models. Intravenous administration of 3, and several analogues, to guinea pigs caused hypotension and electrocardiogram abnormalities. Such cardiovascular side effects were also observed with some nonguanidine inhibitors and inhibitors having recognition motifs other than D-Phe-Pro-Arg. 2-Benzothiazolecarboxylates 4 and 68 exhibited significantly diminished cardiovascular side effects, and benzothiazolecarboxylic acid 4 had the best profile with respect to therapeutic index. The X-ray crystal structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S1′ region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate of 4 forms a salt bridge with the side chain of Lys-60F such that it adopts an extended anti conformation. Since 3 has a 10-fold greater affinity for thrombin than does 4, any increase in binding energy resulting from this salt bridge is apparently offset by perturbations across the enzyme (viz. Figure 4). The increased affinity and selectivity of 2-ketobenzothiazole inhibitors, such as 3, may be primarily due to the aromatic stacking interaction with Trp-60D. However, energy contour calculations with the computer program GRID also indicate a favorable interaction between the benzothiazole sulfur atom and a hydrophobic patch on the surface of thrombin.
Molecular design and structure - Activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664
Das, Jagabandhu,Kimball,Hall, Steven E.,Han, Wen-Ching,Iwanowicz, Edwin,Lin, James,Moquin, Robert V.,Reid, Joyce A.,Sack, John S.,Malley, Mary F.,Chang, Chiehying Y.,Chong, Saeho,Wang-Iverson, David B.,Roberts, Daniel G.M.,Seiler, Steven M.,Schumacher, William A.,Ogletree, Martin L.
, p. 45 - 49 (2007/10/03)
A series of structurally novel small molecule inhibitors of human α-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human α-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.
Novel Amidine-Containing Peptidyl Phosphonates as Irreversible Inhibitors for Blood Coagulation and Related Serine Proteases
Oleksyszyn, Jozef,Boduszek, Bogdan,Kam, Chih-Min,Powers, James C.
, p. 226 - 231 (2007/10/02)
A series of new peptidyl(α-aminoalkyl)phosphonate diphenyl esters containing the 4-amidinophenyl group were synthesized and tested as irreversible inhibitors for thrombin and other trypsin-like enzymes.These phosphonates irreversibly inhibited several coa
CONFIGURATIONAL REQUIREMENTS OF AROMATIC AMINO ACID RESIDUES FOR THE ACTIVITY OF PRP-HEXAPEPTIDE
Kubik, Aleksandra,Szewczuk, Zbigniew,Siemion, Ignacy,Wieczorek, Zbigniew,Spiegel, Krystyna,et al.
, p. 2583 - 2590 (2007/10/02)
The three analogues with D-amino acid substituents at position 1 and 5 of PRP-hexapeptide were synthesized and tested for its biological activity to check the influence of the spatial orientation of aromatic rings on the immune response.One of the analogs
Synthesis and properties of gramicidin S analogs containing Pro-D-Phe sequence in place of D-Phe-Pro sequence in the β-turn part of the antibiotic
Tamaki,Takimoto,Muramatsu
, p. 1469 - 1472 (2007/10/02)
Two analogs of gramicidin S, [L-Pro4, D-Phe5]-gramicidin S and [L-Pro(4,4'), D-Phe(5,5')]-gramicidin S, were synthesized in order to investigate the relationships among positions of Pro residues, antibiotic activity and CD spectra. [
