Improved pharmacophore description of P-glycoprotein modulators

Cancer is one of the diseases with increased prevalence in the 21st century. Since the 1970s that a class of transmembranar proteins called ABC transporters are known, being P-Glycoprotein (Pgp) the most representative member. They are often involved in the efflux of drugs preventing their accumulation in the cytoplasm and thus decreasing the therapeutic effect. This key factor strongly contributes to the phenomena of resistance to anticancer drugs, preventing the success of chemotherapy regimens [1]. Despite the recent publication of the murine P-gp crystallographic structure, the characterization of the drug-binding site is still limited and, therefore, the theories for the protein's functioning cannot be validated and more suitable modulators for the effective inhibition of the multidrug-resistance phenomenon cannot be developed. In this case, pharmacophores can give important input on the subject matter.

Several pharmacophores were already published that identified hydrophobic and acceptor/donor groups as essential characteristics for the recognition by the transporter [2,3]. However, the majority of the already published pharmacophores only cover a small variety of compounds, frequently derived from a primary scaffold, not being able to detect different structures or to select from a database only the active ones. In addition, the literature-derived pharmacophores fail to detect our in-house macrocyclic diterpenes [4].

Inspired on the published literature and based on the lathyrane-type scaffold, we developed a new pharmacophore (Figure 1) capable of detecting not only the literature (84.2%) but also all in-house compounds, with lower detection of inactive molecules, in a database comprising 272 compounds.

Figure 1: In-house pharmacophore

Keywords: P-glycoprotein; pharmacophore; modulators; lathyrane; macrocyclic diterpenes

Acknowledgement: This work was supported by Fundação para a Ciência e Tecnologia (FCT) (Project PTDC/QUI-QUI/099815/2008)

References: 1. Tsuruo T et al. (1981) Cancer Research 41: 1967–1972

2. Pearce HL et al. (1989) Proc Natl Acad Sci USA 86: 5128–5132

3. Pajeva IK.et al. (2002)J Med Chem 45: 5671–5686

4. Duarte N et al. (2006) Planta Med 72(2): 162–168