Rational drug design applied to the search for candidates to reverse multidrug resistance mediated by P-Glycoprotein

BARBIERI, CECILIA L.; LANZA, PRISCILA A.; LAIOLO, JERÓNIMO; CARPINELLA, MARIA CECILIA; ATHANASSOPOULOS, CONSTANTINOS; VERA, D. MARIANO A.

Congreso; 3rd Women in Bioinformatics and Data Science LA Conference; 2022

Women in Bionformatics and Data Science LA

Recently, a detailed description of the binding dynamics of the P-gp by a panel of quinolin-2-ones / pyrimidines hybrids together with inhibitors of known power and substrates have revealed important features related to the spatial arrangements of hydrophobic and methoxy groups and flexibility that would confer inhibitory activity to these compounds.1 Those results have also demonstrated a remarkable superposition between the binding mode predicted for doxorubicin with those found in the experimental structures of the complexes with taxol2 and vincristine3 , confirming the predictions made by the present mixed protocol of docking and molecular dynamics years before the appearance of these structures.We have also informed that the natural product betulin, from Ligaria cuneifolia, efficiently inhibits the efflux of doxorubicin mediated by P-gp.4 We here present 30 derivatives of betulin that were rationally designed in the light of the structural features identified in these previous works.1,4 At least two of them showed an inhibitory potency comparable to tariquidar, a powerful 3rd generation inhibitor unavailable for clinical trials due to its high toxicity. In contrast, most derivatives exhibited low or null toxicity. Although unusual for a promiscuous ABC transporter such as P-gp, best compounds showed specificity for certain contacts in the previously described region1 involving alpha-helices 4-6, 7 and 12. In fact, compounds that had affinity for another site of the transmembrane domain site lack activity, regardless of their free energies of binding.