A synthetic concept is presented that allows the construction of peptide isostere libraries through polymer-supported C-acylation reactions. A phosphorane linker reagent is used as a carbanion equivalent; by employing MSNT as a coupling reagent, the C-acylation can be conducted without racemization. Diastereoselective reduction was effected with L-selectride. The reagent linker allows the preparation of a norstatine library with full variation of the isosteric positions including the P1 side chain that addresses the protease S1 pocket. Therefore, the concept was employed to investigate the P1 site specificity of peptide isostere inhibitors systematically. The S1 pocket of several aspartic proteases including plasmepsin II and cathepsin D was modeled and docked with approximately 500 amino acid side chains. Inspired by this virtual screen, a P1 site mutation library was designed, synthesized, and screened against three aspartic proteases (plasmepsin II, HIV protease, and cathepsin D). The potency of norstatine inhibitors was found to depend strongly on the P1 substituent. Large, hydrophobic residues such as biphenyl, 4-bromophenyl, and 4-nitrophenyl enhanced the inhibitory activity (IC50) by up to 70-fold against plasmepsin II. In addition, P1 variation introduced significant selectivity, as up to 9-fold greater activity was found against plasmepsin II relative to human cathepsin D. The active P1 site residues did not fit into the crystal structure; however, molecular dynamics simulation suggested a possible alternative binding mode.
"Drug development efforts targeting the plasmepsins have been facilitated by previous studies on other aspartic proteases, particularly renin and cathepsin, which have provided most of the inhibitors used in the crystallographic studies. There have been many works that applied to the plasmepsins case some of the above-mentioned docking software; among the most used are AutoDock [29, 93–96], Gold [55–58], and FlexX [29, 64, 67]. These programs have been employed principally to obtain complexes structures that helped to the interpretation of the experimental results; for the screening of different combinatorial libraries of ligands and to generate plasmepsin-substrate conformations used to establish the enzyme reaction mechanism . "
[Show abstract][Hide abstract] ABSTRACT: The development of efficient and selective antimalariais remains a challenge for the pharmaceutical industry. The aspartic proteases plasmepsins, whose inhibition leads to parasite death, are classified as targets for the design of potent drugs. Combinatorial synthesis is currently being used to generate inhibitor libraries for these enzymes, and together with computational methodologies have been demonstrated capable for the selection of lead compounds. The high structural flexibility of plasmepsins, revealed by their X-ray structures and molecular dynamics simulations, made even more complicated the prediction of putative binding modes, and therefore, the use of common computational tools, like docking and free-energy calculations. In this review, we revised the computational strategies utilized so far, for the structure-function relationship studies concerning the plasmepsin family, with special focus on the recent advances in the improvement of the linear interaction estimation (LIE) method, which is one of the most successful methodologies in the evaluation of plasmepsin-inhibitor binding affinity.
Journal of Tropical Medicine 07/2011; 2011(1687-9686):657483. DOI:10.1155/2011/657483
[Show abstract][Hide abstract] ABSTRACT: We have developed a short and highly efficient synthetic strategy towards the hitherto hardly known 3,5- and 3,6-disubstituted 2,3,4,7-tetrahydro-1H-azepine scaffold via a ring-closing metathesis approach utilizing inexpensive and readily available starting material such as methyl acrylate and allylamine. Both seven-membered azacycle scaffolds bearing suitable functional groups, which can easily be modified by means of standard synthetic chemistry, serve as non-peptidic heterocyclic core structures for the further design and synthesis of aspartic protease inhibitors. Through specific decoration with appropriate side chains, individual inhibitors can be tailored with respect to selectivity towards particular family members. A first generation of this class of non-peptidic inhibitors have been tested against the aspartic proteases Plasmepsin II and HIV-I protease, respectively, showing promising activity as well as selectivity with IC50 values in the micromolar range.
[Show abstract][Hide abstract] ABSTRACT: A novel norstatine derivative, phenylthionorstatine [(2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid; Ptns], containing a hydroxymethylcarbonyl (HMC) isostere was designed, synthesized, and stereochemically determined. Then, Ptns was introduced into the structure of BACE1 inhibitors at the P(1) position. Finally, Ptns was found as a suitable P(1) moiety for potent BACE1 inhibitor design.
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