Structure-activity relationship: analyses of p-glycoprotein substrates and inhibitors

Abstract

A highly effective p-gp modulator candidate should possess a log P value of 2.92 or higher, 18-atom-long or longer molecular axis, and a high Ehomo value, as well as at least one tertiary basic nitrogen atom. The results obtained may be useful in explaining drug-p-gp interactions for different compounds, including drug interactions and the development of new MDR chemosensitizers.

The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines

“…Recent photoaffinitylabeling studies suggest there are at least four different drugbinding sites to Pgp. 24,25 The interaction of these sites may account for the wide range of functionally and structurally distinct Pgp modulators and substrates. Despite the fact that most Pgp substrates share certain chemical features, Pgp modulators have been grouped into seven structural categories.…”

“…Despite the fact that most Pgp substrates share certain chemical features, Pgp modulators have been grouped into seven structural categories. 25 Lonafarnib is a structural analog of a calmodulin antagonist, whereas tipifarnib is a heterocyclic imidazolecontaining compound that is similar in structure to the azole antifungals, which are also Pgp inhibitors. 25,26 Therefore, despite possessing both Pgp and FT inhibitory activities, these compounds are unlikely to inhibit Pgp function through interaction at the same drug-binding site.…”

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

“…Reports indicate a strong correlation between physicochemical parameters and MDR1 inhibition. An MDR1 modulator is considered a good candidate if it possesses a log p value of 2.92 or higher, a molecular axis of 18 or more atoms in length, one or more tertiary basic nitrogen atoms, and high energy in its highest occupied orbit [66].…”

Anti-Proliferative effect of ursolic acid on multidrug resistant hepatoma cells R-HepG2 by apoptosis induction

“…P-gp plays an important role on the resistance towards a wide range of chemotherapeutic drugs on many cancer cases. [28][29][30][31] In our study, the ability of circumventing drug resistance by UA was assessed on the P-gp overexpressed cell line R-HepG2. Verapamil (P-gp inhibitor) could not increase the cytotoxicity of UA, but increased the cytoxicity of Dox (P-gp substrate) on R-HepG2 cells (Table 1).…”