Computer-aided discovery of Smac-mimetics within the plant kingdom

Pharmacophore-based virtual screening of natural product databases is an efficient and trendsetting strategy to exploit nature's multitude of bioactivities [1]. Endogenous Smac (second mitochondrial derived activator of caspase) binds at the Bir3 domain of XIAP (X-linked inhibitor of apoptosis protein) and induces apoptosis in this way. Using a computational approach we intend to isolate new potent Smac-mimetics for the discovery of chemosensitizers upon treatment with conventional chemotherapeutics [2].

In a previous study, a pharmacophore model of the Bir3 domain was generated and validated [3]. Commercial databases were virtually screened and synthetic hits were tested on their XIAP inhibition properties. Based on these experimental data, the validated model was refined in this work. Virtual screening filtering experiments were conducted using two in-house made 3D multi-conformational databases of natural molecules designated INP (>110 000 compounds) and DIOS (>9 000 natural products from medicinal plants) [4]. The databases produced hit rates of 0.65% (713 hits) and 0.24% (22 hits), respectively. A first evaluation of the hit lists disclosed some well-known phytochemical classes of higher plants such as acetogenins, terpenoids, alkaloids and lignans. Among the obtained virtual hits 18.6% of the constituents of higher plants are already described in literature to act as cytotoxic, apoptotic, anti-neoplastic or anti-tumor natural agents. In order to verify this computer-aided strategy, compounds of interest will be analyzed from the plant matrix by LC-MS and phytochemically enriched and/or isolated by different chromatographic methods. In further studies, the isolated compounds will be tested in wild type and XIAP overexpressing human leukemia S-Jurkat cells for their potential to induce apoptosis either alone or when combined with low doses of etoposide in order to identify etoposide specific chemosensitizers.

References: [1] Rollinger, J.M. et al. (2006) Planta Med. 72: 671–678. [2] Fulda, S. et al. (2002) Nat. Med. 8: 808–815. [3] Bliem, C.B. et al. (2006) Planta Med. 72, P084: 1008. [4] Rollinger, J.M. et al. (2004) J. Chem. Inf. Comput. Sci. 44: 480–488.