Thrombin docking

Bohm HJ, Banner DW, Weber L. Combinatorial docking and combinatorial chemistry design of potent non-peptide thrombin inhibitors. J Comput Aided Mol Design 1999 13 51-6. 

Frederick, R. Robert, S. Charlier, C. de Ruyck, J. Wouters, J. Masereel, B. Pochet, L. Mechanism-based thrombin inhibitors design, synthesis, and molecular docking of a new selective 2-OXO-2/7- l-benzopyxan derivative. J. Med. Chem. 2007, 50, 3645-3650. 

Bohm described combinatorial docking [272] implemented in LUDI [216] for reductive amination in search for thrombin inhibitors. The binding mode of the most active one with a Ki value of 95 nM was even confirmed by X-ray structure analysis [234] (see Figure 4.5e). 

At this point, we had assembled a preliminary model of the human thrombin receptor that contained all three extracellular loops linked to the seven TM domains, as well as the N-terminus out to residue 75. Docking studies with agonist peptide SFLLRN, and additional mutagenesis experiments, were carried out in parallel. Measurement of the effects of site-specific mutations in human PAR-1 identified several key amino acids of the receptor as being important for activation (Table 1),... 

Figure 2.130. (vida docking) Visual inspection of the interactions of a ligand, napap, in the active site of a protein, thrombin... 

Murray CW, Baxter CA, Frenkel AD (1999) The sensitivity of the results of molecular docking to induced fit effects application to thrombin, thermolysin and neuraminidase. J Comput Aided Mol Des 13(6) 547-562... 

Combinatorial Docking and Combinatorial Chemistry Design of Potent Non-Peptide Thrombin Inhibitors. 

The Sensitivity of the Results of Molecular Docking to Induced Fit Effects Application to Thrombin, Thermolysin and Neuraminidase. 

P. D. J. Grootenhuis,. Comput.-Aided Mol. Des., 13, 167 (1999). Comparison of Two Implementations of the Incremental Construction Algorithm in Flexible Docking of Thrombin Inhibitors. 

The difficulties associated with weak binders are illustrated in Figure 7 with thrombin as a target. The 7500 compound subset of the WDI mentioned above was docked into the thrombin active site together with three sets of 100... 

Thrombin inhibitors (127), where Bohm et al. used LUDI to dock and score computationally available primary amines and then score the virtual library generated from benzaldehydes with the top-scoring hit. 

Other type III peptidomimetic inhibitors of thrombin have been developed from screening leads (166, 167) such as inhibitor (94) (Fig. 15.40). SAR led to the design of (95)Inhibitor (96) was derived from docking studies with the 5-amidino indole nucleus, followed by addition of a lipophilic side-chain to interact with the important Sg subsite of thrombin. The crystal structures of both (95) and (96) in the active site of thrombin shows that the aromatic core, binds in the site as expected, but... 

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