QSAR studies on P-glycoprotein-regulated multidrug resistance and on its reversal by phenothiazines.
Multidrug resistance is brought about largely by membrane transport proteins such as P-glycoprotein (P-gp). We have developed a quantitative structure-activity relationship (QSAR) for P-gp-associated ATPase activity for a diverse set of 22 drugs, and found that such activity is related to substrate molecular size and polarity. We have also developed a QSAR for drug efflux from the blood-brain barrier of another diverse set of 22 drugs, and found that such efflux is a function of drug size and polarisability. Thirdly, we have carried out a QSAR analysis of the ability of 157 phenothiazines and related drugs to reverse multidrug resistance. We were unable to obtain a good QSAR for the whole data-set, but when we divided the data-set into sub-sets of closely related structures, a series of good correlations was obtained, most of which incorporated descriptors that model molecular size and polarity/polarisability. In no instance did we find any evidence that hydrogen bonding or hydrophobicity play a part in multidrug resistance or its reversal, despite that fact that several other workers have reported that these effects appear to be important here.
Dearden
J C
JC
School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK. j.c.dearden@livjm.ac.uk
Al-Noobi
A
A
Scott
A C
AC
Thomson
S A
SA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D000251:Adenosine Triphosphatases / Q000494:pharmacology; D001812:Blood-Brain Barrier; D018432:Drug Resistance, Multiple; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010640:Phenothiazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010640:Phenothiazines; D000251:Adenosine Triphosphatases