Pharmacophore protease inhibitors

Today, 3D databases, which provide the means for storing and searching for 3D information of compounds, are proven to be useful tools in drug discovery programs. This is well exemplified with the recent discovery of novel nonpeptide HIV-1 protease inhibitors using pharmacophore searches of the National Cancer Institute 3D structural database [13-15]. 

Steindl, T.M., Schuster, D., Laggner, C., Chuang, K., Hoffmann, R.D. and Langer, T. (2007) Parallel Screening and Activity Profiling with HIV Protease Inhibitor Pharmacophore Models. Journal of Chemical Information and Modeling,... 

Milne et al. described the discovery of HIV-1 protease inhibitors based on a pharmacophore derived from X-ray crystal structures. After searching the NCI database with 206 000 entries and postfiltering the resulting hits, a total of 50 molecules were tested, leading to submicromolar activity for the best two compounds [286]. In their search for HIV-1 integrase inhibitors, another pharmacophore produced up to 340 hits, resulting in 10 structurally different classes and four compounds with affinities below 30 XM [287]. 

In a paper published in 2000 by Norinder [30], Catalyst was used for the first time to build a common feature pharmacophore hypothesis for HIV-1 protease inhibitors, which was then refined using in-house software (HypoOpt), after having added to it some hundreds of excluded volume spheres. These were actually derived from the X-ray structure of an inhibitor complexed to the enzyme. The aim of the approach was to obtain a computational model with some improved predictive power with respect to the corresponding hypothesis derived without receptor information. 

The multiple potential pharmacophores for targets, such as protein active sites, are defined using complementary site points to exposed features accessible in the site. These site points (see section 2.3) create a hypothetical molecule that interacts with all pharmacophoric regions of the site. Figure 2 illustrates site points that were used for the thrombin site in selectivity studies for three serine protease inhibitors (see section 4.3). The potential pharmacophores are calculated for this molecule just as for any... 

Five-membered ring heterocycles are common in numerous pharmaceuticals. In particular, the imidazole core structure, an element of histidine and its decarboxylation metabolite histamine, is often found [53]. The exceptional properties and wide applicability of the imidazole pharmacophore are due to its hydrogen-bond donor/acceptor capabilities and its high affinity for metals (present in many protein active sites, e.g., Zn, Fe, Mg) [54-58]. In addition, peptide-based protease inhibitors with improved pharmacokinetics and bioavailability have been obtained by replacing an amide bond with an imidazole [59]. 

Wang et al. reported the application of an X-ray structure-derived pharmacophore model to identify novel HIV-1 protease inhibitors. After searching the NCI database (206 000 molecules), testing of 50 molecules resulted in submicromolar activity for the best 2 compounds [149]. In a search for HIV-1 integrase inhibitors, a protein-derived pharmacophore mode] produced 340 hits from 10 different classes. Four compounds vere sho vn to have affinities <30 pM [150] against this enzyme. 

Posey I., Nicklaus, M.C., Graham, L., and Rice, W.G. (1996) Discovery of novel, non-peptide HIV-1 protease inhibitors by pharmacophore searching. Journal of Medicinal Chemistry, 39, 2047-2054. 

Figure 4. Schematic representation ofAcivicin s mode of action as well as that of other amidotransferase inhibitors, where X is the pharmacophoric moiety of cysteine protease inhibitors.

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