Pharmacophore Model of Drugs Involved in P-Glycoprotein Multidrug Resistance:  Explanation of Structural Variety (Hypothesis)

Pajeva, Ilza; Wiese, Michael

doi:10.1021/jm020941h

Cited by 149 publications

(145 citation statements)

References 38 publications

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“…Later, they conducted pharmacophore modeling research of drugs involved in Pgp multidrug resistance using the genetic algorithm similarity program (GASP) pharmacophore modeling tool. 82 In a widely cited study, Seelig identifi ed 2 recognition elements for Pgp that were composed of hydrogen bond acceptors with distinct spatial arrangements. 90 Seelig referred to 2 hydrogen bond acceptors separated by ~2.5 Å as a Type I pattern; Type II patterns are formed by 2 hydrogen bond acceptors separated by ~4.6 Å, or 3 hydrogen bond acceptors separated by ~2.5 Å with a 4.6 Å separation of the outer 2 acceptor groups.…”

Section: Modeling Of P-glycoprotein Substrates and Inhibitorsmentioning

confidence: 99%

Recent progress in the computational prediction of aqueous solubility and absorption

Johnson

Zheng

2006

AAPS J

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The computational prediction of aqueous solubility and/or human absorption has been the goal of many researchers in recent years. Such an in silico counterpart to the biopharmaceutical classifi cation system (BCS) would have great utility. This review focuses on recent developments in the computational prediction of aqueous solubility, P-glycoprotein transport, and passive absorption. We fi nd that, while great progress has been achieved, models that can reliably affect chemistry and development are still lacking. We briefl y discuss aspects of emerging scientifi c understanding that may lead to breakthroughs in the computational modeling of these properties.

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Section: Modeling Of P-glycoprotein Substrates and Inhibitorsmentioning

confidence: 99%

Recent progress in the computational prediction of aqueous solubility and absorption

Johnson

Zheng

2006

AAPS J

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“…While relative lipophilicity, the presence of a basic nitrogen atom and molecular refractivity have been suggested to be important factors for efficient interaction of an MDR reversing agent with Pglycoprotein [154,155], the structural determinants or pharmacophore of chemically and pharmacologically diverse MDR modulators remain largely unknown. However, several reports have further defined important features of P-glycoprotein pharmacophore [156][157][158][159][160][161][162][163][164][165][166]. Recent structure-activity relationship studies ot P-glycoprotein substrates and modifiers indicate that if two substrates are applied simultaneously to P-glycoprotein, the compound with the higher potential to form hydrogen bonds generally acts as an inhibitor [159].…”

Section: Specific Inhibitorsmentioning

confidence: 99%

“…In support of this idea, Pajeva and Wiese [161] recently proposed a general pharmacophore model of P-glycoprotem drugs that is based on a highly diverse data set and relates to the verapamil-binding site of the protein. The pharmacophore model consists of two hydrophobic points, three hydrogen bond (HB) acceptor points, and one HB donor point.…”

Section: Specific Inhibitorsmentioning

confidence: 99%

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Safa

2004

CMCACA

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A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance (MDR) is overexpression of the MDR1 product P-glycoprotein, known to bind to and transport a wide variety of agents. This review concentrates on the progress made toward understanding the role of this protein in MDR, identifying and characterizing the drug binding sites of P-glycoprotein, and modulating MDR by P-glycoprotein-specific inhibitors. Since our initial discovery that Pglycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein-specific photoaffinity analogs have been developed and used to identify the particular domains of Pglycoprotein capable of interacting with these analogs and other P-glycoprotein substrates. Furthermore, significant advances have been made in delineating the drug binding sites of this protein by studying mutant P-glycoprotein. Photoaffinity labeling experiments and the use of sitedirected antibodies to several domains of this protein have allowed the localization of the general binding domains of some of the cytotoxic agents and MDR modulators on P-glycoprotein. Moreover, site-directed mutagenesis studies have identified the amino acids critical for the binding of some of these agents to P-glycoprotein. Furthermore, equilibrium binding assays using plasma membranes from MDR cells and radioactive drugs have aided our understanding of the modes of drug interactions with P-glycoprotein. Based on the available data, a topological model of Pglycoprotein and the approximate locations of its drug binding sites, as well as a proposed classification of multiple drug binding sites of this protein, is presented in this review.

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“…Iako je ovaj model razvijen korišćenjem relativno malog broja struktura, naš rad na razvoju modela za transport Pgp-om ukazao je da trodimenzionalni deskriptori izvedeni iz predloženih farmakofora mogu značajno unaprediti predviđanja globalnih modela [47]. Većina drugih farmakofornih modela u literaturi predložena je za specifična, pretpostavljena vezivna mesta Pgp-a [69][70][71]. Do sada predloženi globalno primenjivi farmakoforni modeli zasnivaju se na pristupu koriščenja skupa (ansambla) velikog broja pojedinačnih farmakofora.…”

Section: Modeli Zasnovani Na Farmakofornim Hipotezamaunclassified

Computational models for predicting drug transport mediated by P-glycoprotein

Erić¹,

Kalinić²

2015

Arh farmaciju

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Kratak sadržajP-glikoprotein (Pgp) je transmembranski transporter koji, transportujući strukturno raznovrsne lekove iz unutrašnjosti ćelije u ekstracelularnu sredinu, može uticati na resorpciju, distribuciju i efikasnost većeg broja lekova. Prekomerna ekspresija Pgp-a u ćelijama predstavlja jedan od mehanizama razvoja rezistencije na lekove. Iz ovih razloga, potrebno je u ranoj fazi otkrića leka predvideti da li je potencijalni lek supstrat za Pgp, idealno i pre same sinteze. U tu svrhu, tokom poslednje decenije razvijen je veliki broj računarskih modela koji omogućavaju predviđanje transporta posredstvom Pgp-a samo na osnovu hemijske strukture. U ovom radu prikazan je pregled različitih pristupa koji su korišćeni u razvoju modela, razmotrene su njihove prednosti i nedostaci, kao i faktori koji u najvećoj meri utiču na pouzdanost predviđanja. Polispecifičnost ovog transportera predstavlja značajan izazov za većinu metoda računarske hemije. Ipak, dostignut nivo tačnosti modela koji su prikazani u litearaturi ukazuje na činjenicu da oni mogu doprineti racionalizaciji procesa dizajniranja novih lekova. Šira dostupnost eksperimentalnih podataka, kao i kombinovanje različitih pristupa modelovanju transporta, mogu dodatno unaprediti postojeće modele.Ključne reči: P-glikoprotein, računarski modeli, rezistencija, dizajn lekova.

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Pharmacophore Model of Drugs Involved in P-Glycoprotein Multidrug Resistance: Explanation of Structural Variety (Hypothesis)

Cited by 149 publications

References 38 publications

Recent progress in the computational prediction of aqueous solubility and absorption

Recent progress in the computational prediction of aqueous solubility and absorption

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

Computational models for predicting drug transport mediated by P-glycoprotein

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