scholarly journals Development of modulators of multidrug resistance: A pharmacoinformatic approach

2004 ◽  
Vol 76 (5) ◽  
pp. 997-1005 ◽  
Author(s):  
G. F. Ecker ◽  
Peter Chiba
Keyword(s):  
Neural Networks ◽  
Multidrug Resistance ◽  
Molecular Basis ◽  
Tumor Therapy ◽  
3D Qsar ◽  
Drug Efflux ◽  
Qsar Studies ◽  
P Glycoprotein ◽  
Drug Efflux Pumps ◽  
2D And 3D

Inhibition of drug efflux pumps such as P-glycoprotein represents a versatile approach for overcoming multidrug resistance in tumor therapy. Although numerous compounds have been identified as being able to inhibit P-glycoprotein, only little is known on the molecular basis of the drug–protein interaction. This article gives an overview of the different pharmacoinformatic approaches we used to develop new propafenone-type modulators of P-glycoprotein. These include 2D-and 3D-QSAR studies, artificial neural networks, and photoaffinity labeling studies.

scholarly journals 2D- and 3D-QSAR studies of a series of benzopyranes and benzopyrano[3,4b][1,4]-oxazines as inhibitors of the multidrug transporter P-glycoprotein

2013 ◽  
Vol 27 (2) ◽  
pp. 161-171 ◽  
Author(s):  
Ishrat Jabeen ◽  
Penpun Wetwitayaklung ◽  
Peter Chiba ◽  
Manuel Pastor ◽  
Gerhard F. Ecker
Keyword(s):  
3D Qsar ◽  
Multidrug Transporter ◽  
Qsar Studies ◽  
P Glycoprotein ◽  
2D And 3D

scholarly journals Targeting drug-efflux pumps -- a pharmacoinformatic approach.

2005 ◽  
Vol 52 (3) ◽  
pp. 737-740 ◽  
Author(s):  
Karin Pleban ◽  
Dominik Kaiser ◽  
Stefan Kopp ◽  
Michael Peer ◽  
Peter Chiba ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Molecular Basis ◽  
Screening Tools ◽  
Drug Efflux ◽  
Transmembrane Helices ◽  
Binding Region ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Drug Efflux Pumps ◽  
Labeling Pattern

In line with our studies on propafenone-type inhibitors of P-glycoprotein (P-gp), we applied several methods to approach virtual screening tools for identification of new P-gp inhibitors on one hand and the molecular basis of ligand-protein interaction on the other hand. For virtual screening, a combination of autocorrelation vectors and selforganising artificial neural networks proved extremely valuable in identifying P-gp inhibitors with structurally new scaffolds. For a closer view on the binding region for propafenone-type ligands we applied a combination of pharmacophore-driven photoaffinity labeling and protein homology modeling. On LmrA, a bacterial homologue of P-gp, we were able to identify distinct regions on transmembrane helices 3, 5 and 6 which show significant changes in the labeling pattern during different steps of the catalytic cycle.

Synthesis, cytotoxic activity, and 2D- and 3D-QSAR studies of 19-carboxyl-modified novel isosteviol derivatives as potential anticancer agents

2017 ◽  
Vol 89 (6) ◽  
pp. 870-887 ◽  
Author(s):  
Cong-Jun Liu ◽  
Tao Zhang ◽  
Shu-Ling Yu ◽  
Xing-Jie Dai ◽  
Ya Wu ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Anticancer Agents ◽  
3D Qsar ◽  
Qsar Studies ◽  
2D And 3D

Drug efflux mediated by the human multidrug resistance P-glycoprotein is inhibited by cell swelling

1994 ◽  
Vol 107 (12) ◽  
pp. 3281-3290
Author(s):  
A. Sardini ◽  
G.M. Mintenig ◽  
M.A. Valverde ◽  
F.V. Sepulveda ◽  
D.R. Gill ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Chloride Channels ◽  
Drug Transport ◽  
Atp Hydrolysis ◽  
Cell Swelling ◽  
Drug Efflux ◽  
Fluorescent Substrate ◽  
Membrane Stretch ◽  
P Glycoprotein ◽  
In Cells

P-glycoprotein (P-gp), the product of the human multidrug resistance (MDR1) gene, confers multidrug resistance on cells by acting as an ATP-dependent drug transporter. A method using confocal microscopy was developed to measure the transport activity of P-gp from the rate of movement of doxorubicin, a fluorescent substrate of P-gp, across the membrane of a single cell. Recent work has shown that expression of P-gp enhances the activation of chloride channels in response to cell swelling, suggesting that membrane stretch might switch P-gp from a drug-transporting mode to a mode in which it activates chloride channels. In agreement with this idea, we find that cell swelling inhibits drug efflux in cells expressing P-gp but is without effect on the slower background efflux in cells not expressing P-gp and in cells transiently transfected with a mutated MDR1 in which the ATP hydrolysis sites had been inactivated. The identification of a novel means for inhibiting P-gp-mediated drug transport may have implications for the reversal of multidrug resistance during chemotherapy.

2D and 3D QSAR Studies on a Series of Antichagasic Fenarimol Derivatives

2017 ◽  
Vol 2 (1) ◽  
pp. 44-63
Author(s):  
Anacleto S. de Souza ◽  
Leonardo G. Ferreira ◽  
Adriano D. Andricopulo
Keyword(s):  
Neglected Tropical Diseases ◽  
Public Health Problem ◽  
Predictive Ability ◽  
3D Qsar ◽  
Structural Features ◽  
Field Analysis ◽  
Global Public Health ◽  
Qsar Studies ◽  
Qsar Models ◽  
2D And 3D

Chagas disease is one of the most important neglected tropical diseases. Endemic in Latin America, the disease is a global public health problem, affecting several countries in North America, Europe, Asia and Oceania. The disease affects around 8-10 million people worldwide and the limited treatments available present low efficacy and severe side effects, highlighting the urgent need for new therapeutic options. In this work, the authors developed QSAR models for a series of fenarimol derivatives exhibiting anti-T. cruzi activity. The models were constructed using the Hologram QSAR (HQSAR), Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods. The QSAR models presented substantial predictive ability for a series of test set compounds (HQSAR, r2pred = 0.66; CoMFA, r2pred = 0.82; and CoMSIA, r2pred = 0.76), and were valuable to identify key structural features related to the observed trypanocidal activity. The results reported herein are useful for the design of novel derivatives having improved antichagasic properties.

scholarly journals Reversal of Mefloquine and Quinine Resistance in Plasmodium falciparum with NP30

2003 ◽  
Vol 47 (8) ◽  
pp. 2393-2396 ◽  
Author(s):  
Michelle Ciach ◽  
Kathleen Zong ◽  
Kevin C. Kain ◽  
Ian Crandall
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Genetic Analysis ◽  
Resistance Genes ◽  
Mammalian Cells ◽  
Point Mutations ◽  
In Vitro Assays ◽  
Drug Efflux ◽  
P Glycoprotein

ABSTRACT Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (mdr) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential Plasmodium falciparum P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%) P. falciparum to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 μM verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in pfcrt and pfmdr1 and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.

Volume Learning Algorithm Artificial Neural Networks for 3D QSAR Studies

2001 ◽  
Vol 44 (15) ◽  
pp. 2411-2420 ◽  
Author(s):  
Igor V. Tetko ◽  
Vasyl V. Kovalishyn ◽  
David J. Livingstone
Keyword(s):  
Neural Networks ◽  
Artificial Neural Networks ◽  
Learning Algorithm ◽  
3D Qsar ◽  
Qsar Studies ◽  
Artificial Neural
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