59515-79-6Relevant articles and documents
Development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors: Biological evaluation and structural characterization by cocrystallization
Addlagatta, Anthony,Ding, Yongzheng,Ma, Chunhua,Marapaka, Anil Kumar,Pillalamarri, Vijaykumar,Reddi, Bharati,Sankoju, Priyanka,Sijwali, Puran Singh,Sudhakar, Renu,Zhang, Guozhen,Zhang, Yingjie
, (2021/12/01)
Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use, including the artemisinin-based combinations, which are the last line of defense against malaria. This necessitates the discovery of new targets and the development of novel antimalarials. Plasmodium falciparum alanyl aminopeptidase (PfA-M1) and leucyl aminopeptidase (PfA-M17) belong to the M1 and M17 family of metalloproteases respectively and play critical roles in the asexual erythrocytic stage of development. These enzymes have been suggested as potential antimalarial drug targets. Herein we describe the development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors. Most of the compounds described in this study display inhibition at sub-micromolar range against the recombinant PfA-M1 and PfA-M17. More importantly, compound 26 not only exhibits potent malarial aminopeptidases inhibitory activities (PfA-M1 Ki = 0.11 ± 0.0002 μmol/L, PfA-M17 Ki = 0.05 ± 0.005 μmol/L), but also possesses remarkable selectivity over the mammalian counterpart (pAPN Ki = 17.24 ± 0.08 μmol/L), which endows 26 with strong inhibition of the malarial parasite growth and negligible cytotoxicity on human cell lines. Crystal structures of PfA-M1 at atomic resolution in complex with four different compounds including compound 26 establish the structural basis for their inhibitory activities. Notably, the terminal ureidobenzyl group of 26 explores the S2′ region where differences between the malarial and mammalian enzymes are apparent, which rationalizes the selectivity of 26. Together, our data provide important insights for the rational and structure-based design of selective and dual inhibitors of malarial aminopeptidases that will likely lead to novel chemotherapeutics for the treatment of malaria.
Additivity or cooperativity: Which model can predict the influence of simultaneous incorporation of two or more functionalities in a ligand molecule?
Nasief, Nader N.,Hangauer, David
, p. 897 - 915 (2015/05/27)
Predicting how binding affinity responds to ligand structural modifications in structure-activity relationship studies (SAR) is a major challenge in medicinal chemistry. This is particularly true when two or more of these modifications are carried out simultaneously. In this study, we present binding affinity data from several series of thermolysin inhibitors in which simultaneous structural modifications were investigated to determine whether they are cooperative or additive. Data revealed that, while additivity is at work in some cases, cooperativity is more commonly demonstrated. Cooperativity and additivity were then correlated with ligand descriptors, such as the spacing and the topological features of the modified groups, in a manner that may provide guidance as to when each model should be utilized. Cooperativity was particularly associated with contiguous groups and small unbranched hydrophobic side chain. Additivity, on the other hand, was associated with moderately distant hydrophobic group combinations and side chain branching. Such correlations can improve the predictability of SAR studies and can provide a starting point for additional investigations that may lead to further significant enhancements in the current scoring functions.
Synthesis of tri-, penta-, and heptapeptides containing an (R)-2-alkyl-2-amino-3-(methylamino)-propionic acid residue in the central position
Seebach,Studer,Pfammatter,Widmer
, p. 2035 - 2050 (2007/10/02)
By conventional peptide-coupling methods (C to N direction; mixed anhydride, bis(2-oxooxazolidin-3-yl)phosphinoyl chloride (Bop-Cl), or dicyclohexylcarbodiimide (DCC), 2-amino-2-methyl-3-(methylamino)propionic acid and 2-amino-2-ethyl-3-(methylamino)propi
