Authors: Srinivas, E.; Murthy, J. N.; Rao, A. R.R.; Sastry, G. N.

Source: Current Drug Metabolism, Volume 7, Number 2, February 2006 , pp. 205-217(13)

Publisher: Bentham Science Publishers

Abstract:

Phospho-glycoprotein (P-gp) is an efflux transporter expressed in many organs (ex: kidney, lung, liver and spleen) and in hormone producing or responsive tissues (ex: adrenal cortex, testis and placenta). It is involved in many important physiological functions. Among them the major one is extrusion of xenobiotics in order to detoxify the cells. This property of P-gp is associated with multidrug resistance (MDR) for many pathological conditions. While the experimental determination of three-dimensional structure is not yet successful, the transmembrane (TM) 5, 6, 11 and 12 are sensitive to mutations and contain substrate binding sites. Designing of potential and selective inhibitors of P-gp is still hampered by a lack of information upon the three dimensional structure of P-gp. The design of P-gp inhibitors was traditionally driven by quantitative structure activity relationship studies, which is complicated by factors such as different types of assays, multiple drug binding sites and diverse chemical structures. Clearly a conclusive and predictive SAR does not seem to be practical, despite progress in the last few years towards more specific SAR suggesting well defined structural features responsible for activity. Advances made recently in solving the crystal structure of prokaryotic ATP binding cassette proteins (ABC) transporters, Ec-MsbA, Vc-MsbA and BtuCD yielded suitable templates for construction of homology models of P-gp. Few molecular dynamics (MD) simulations aimed at elucidating the functional dynamics of ABC transporters have provided useful insights to their mechanism and structure. The present review aims at the general overview of importance, expression, structure, organization and drug binding sites of P-gp. This review also highlights recent developments in the homology modeling, molecular dynamics simulations of P-gp and progress in QSAR, pharmacophore modeling of P-gp modulators.

Keywords: P-glycoprotein; Transmembrane proteins; Homology modeling; QSAR studies; Molecular descriptors

Document Type: Research article

DOI: http://dx.doi.org/10.2174/138920006775541543

Affiliations: 1: Molecular Modeling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.

Publication date: 2006-02-01

More about this publication?

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

Related content

• In this: publication
• By this: publisher
• In this Subject: Anatomy & Physiology ,  Pharmacology
• By this author: Srinivas, E. ;  Murthy, J. N. ;  Rao, A. R.R. ;  Sastry, G. N.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers