Abstract:
Multidrug resistance (MDR) is a phenomenon associated with resistance of cancer cells to a wide range of structurally and functionally diverse group of drugs thus, contributes as major constituent against chemotherapeutics resistance in cancer cells. Of all the many factors contributing, one is the involvement of multidrug resistance transporter ABCB1 also known as P-glycoprotein (P-gp). P-glycoprotein belongs to ATP binding cassette (ABC) superfamily of transporters and has been reported to show intrinsic and acquired MDR by overexpression in cancer cell and therefore, proven to be promising target against MDR in cancer. In normal physiological conditions, this transporter is responsible for protecting the body against xenobiotic by effluxing them out of the cells. P-glycoprotein, when overexpressed in cancer cells, efflux out the chemotherapeutics along with the xenobiotic diminishing the effectiveness of cancer drugs. That is why P-glycoprotein has emerged as extremely important therapeutic target for enhancing the cancer drugs efficacy by blocking off the P-gp mediated drug efflux. Here in this study, we have built homology model of P-gp along with structural guided GRind Independent Descriptor (GRIND) model based on natural inhibitors of P-gp given their activity from higher nanomolar to lower micromolar range and less toxicity.
Molecular shape/surface hydrophobicity along with hydrogen bond donor feature at 16.80 - 17.20Å distance, and hydrophobic and donor group at 15.20 - 15.60Å indicated positive contribution of these molecular features at these particular distances in potent chemical compounds. Meanwhile, two donor groups at 7.20 - 7.60Å contributed negatively in P-gp inhibitors reducing their efficacy therefore, were present in least potent inhibitors. Our docking results delineates the interaction of diverse data set with Trp232, Phe336, Gln725, Trp732 Asn839, and Asn842 contributing towards side chain acceptor and π-π interactions.
Four potential hits have been identified by virtual screening of world durg index database. Later, we tested these compounds in LCC6 and LCC6MDR cell lines to estimate their effectiveness against percentage reversal of MDR and reversal of Paclitaxel (PTX) IC50 was calculated in the presence of various concentrations of predicted hits. Further optimization of these compounds will be a step forward to improve the efficacy of chemical compounds against cancer related MDR.
