title: 3D-QSAR AND CONTOUR MAP ANALYSIS OF TARIQUIDAR ANALOGUES AS MULTIDRUG RESISTANCE PROTEIN-1 (MRP1) INHIBITORS.
abstract: One of the major obstacles to the successful chemotherapy towards several cancers is multidrug resistance of human cancer cells to anti-cancer drugs. An important contributor to multidrug resistance is the human multidrug resistance protein-1 transporter (MRP1), which is an efflux pump of the ABC (ATP binding cassette) superfamily. Thus, highly efficacious, third generation MRP1 inhibitors, like tariquidar analogues, are promising inhibitors of multidrug resistance and are under clinical trials. To maximize the efficacy of MRP1 inhibitors and to reduce systemic toxicity, it is important to limit the exposure of MRP1 inhibitors and anticancer drugs to normal tissues and to increase their co-localization with tumor cells. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) associated with 3D-Quantitiative structure-activity relationship (3D-QSAR) studies were performed on a series of tariquidar analogues, as selective MDR modulators. Best predictability was obtained with CoMFA modelr2(non-cross-validated square of correlation coefficient) = 0.968,Fvalue = 151.768 with five components, standard error of estimate = 0.107 while the CoMSIA yieldedr2= 0.982,Fvalue = 60.628 with six components, and standard error of estimate = 0.154. These results indicate that steric, electrostatic, hydrophobic (lipophilic), and hydrogen bond donor substituents play significant roles in multidrug resistance modulation of tariquidar analogues upon MRP1. The tariquidar analogue and MRP1 binding and stability data generated from CoMFA and CoMSIA based 3D-contour maps may further aid in study and design of tariquidar analogues as novel, potent and selective MDR modulator drug candidates.
authors.affiliation: Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
authors.forename: Prathusha
authors.initials: P
authors.lastname: Kakarla
authors.affiliation: Department of Biological Sciences, College of Arts and Sciences, University of North Texas, 1155 Union Circle #305220, Denton, TX 76203, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Inupakutika
authors.affiliation: Department of Biological Sciences, College of Arts and Sciences, University of North Texas, 1155 Union Circle #305220, Denton, TX 76203, USA.
authors.forename: Amith R
authors.initials: AR
authors.lastname: Devireddy
authors.affiliation: Bioinformatics Division, Osmania University, Hyderabad-500007, Andhra Pradesh, India.
authors.forename: Shravan Kumar
authors.initials: SK
authors.lastname: Gunda
authors.affiliation: Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
authors.forename: Thomas Mark
authors.initials: TM
authors.lastname: Willmon
authors.affiliation: Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Ranjana
authors.affiliation: Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
authors.forename: Ugina
authors.initials: U
authors.lastname: Shrestha
authors.affiliation: Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
authors.forename: Indrika
authors.initials: I
authors.lastname: Ranaweera
authors.affiliation: Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Hernandez
authors.affiliation: Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
authors.forename: Sharla
authors.initials: S
authors.lastname: Barr
authors.affiliation: Department of Biology, Eastern New Mexico University, Station 33, Portales, NM, 88130, USA.
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Varela
keywords: ABC transporters; Anti-cancer therapy; Cancer; CoMFA; CoMSIA; Contour map analysis; Efflux; Inhibition; MDR; MRP1; Modulation; QSAR; Tariquidar