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Abstract
P-glycoprotein (Pgp), an evolutionary conserved ABC transporter predominantly localized in cell membranes, acts as a gatekeeper regulating the passage of various molecules, including drugs and toxins. The protective physiological function of Pgp against toxic substances can induce multi-drug resistance in chemotherapy. As a result, Pgp-mediated transport presents a formidable hurdle to drug development. The membrane environment plays a significant role in influencing the activity of Pgp. Cholesterol derivatives in the membrane can be flip-flopped between membrane leaflets by Pgp, accounting partially for the traditionally high basal ATPase activity reported. Second, cholesterol derivatives indirectly modulate Pgp activity by providing a conducive conformation of the protein necessary for transport and aiding substrate partitioning into the inter-leaflet space, where Pgp’s binding cavity resides. While inhibiting Pgp is a logical strategy to combat drug resistance, the lack of approved Pgp inhibitors for cancer treatment and the limited success of repurposed FDA-approved drugs as inhibitors in clinical studies present obstacles. An alternative involves redesigning existing drugs to be non-Pgp-substrates, leading to more cost-effective drug design. Interestingly, Pgp-mediated transport rates can differ between drugs of the same class. To better understand this phenomenon and set the tone for rational drug design, we investigated some of the antitumor alkaloids such as the camptothecin analogs (CPTs): topotecan (TPT), SN-38, and irinotecan (IRT); and vinca alkaloids (VAs): vinblastine (VBL) and vinorelbine (VRL) and vincristine (VCR). The action of Pgp has limited the efficacy of these otherwise highly potent chemotherapeutic agents. Conformationally-gated models underlying Pgp-mediated transport of these classes of drugs are presented. Additionally, specific functional groups on the CPTs and VAs that likely interact with Pgp were identified. Our study, when coupled with existing structure-activity relationship investigations, offers a promising path for creating enhanced drug derivatives that could withstand Pgp-mediated efflux.