Combined Pharmacophore Modeling, Docking, and 3D QSAR Studies of ABCB1 and ABCC1 Transporter Inhibitors

Abstract

Quinazolinones, indolo- and pyrrolopyrimidines with inhibitory effects toward ABCB1 (P-gp) and ABCC1 (MRP1) transporters were studied by pharmacophore modeling, docking, and 3D QSAR to describe the binding preferences of the proteins. The pharmacophore overlays between dual and/or highly selective inhibitors point to binding sites of different topology and physiochemical properties for MRP1 and P-gp. Docking of selective inhibitors into the P-gp binding cavity by the use of a structural model based on the recently resolved P-gp structure confirms the P-gp pharmacophore features identified, and reveals the interactions of some functional groups and atoms in the structures with particular protein residues. The 3D QSAR analysis of the dual-effect inhibitors allows satisfactory prediction of the selectivity index of the compounds and outlines electrostatics as most important for selectivity. The results from the combined modeling approach complement each other and could improve our understanding of the protein-ligand interactions involved, and could aid in the development of highly selective and potent inhibitors of P-gp and MRP1.

Substrate recognition by P-glycoprotein efflux transporters: Structure-ATPase activity relationship of diverse chemicals and agrochemicals

“…In addition, from the point of view of early absorption, distribution, metabolism, and excretion (ADME) prediction of therapeutic agents, various computational prediction models have been reported for ligand interactions with P-gp. 2,[4][5][6][7][8][9][10] In general, a P-gp substrate seems to be lipophilic or amphiphilic, having a large size or molecular volume, electronegative groups and hydrogen bonding groups. 11) Although X-ray structures of the complex of mouse P-gp with enantiomeric cyclic peptide inhibitors have been reported previously by Aller et al in 2009, 12) the mechanism of P-gp substrate/inhibitor recognition is complicated and still poorly understood.…”

“…9) We constructed a CoMFA model for ATPase activity produced by DBH derivatives. The model showed sterically and electronically favorable/unfavorable regions for activity.…”

Computational models for predicting drug transport mediated by P-glycoprotein

“…Dostupnost ovih struktura i modela doprinelo je racionalizaciji strukturne osnove različitih eksperimentalnih zapažanja. Više autora primenilo je molekulski doking u predviđanju strukture kompleksa Pgp-a i jedinjenja koja se za transporter vezuju [82][83][84][85][86][87]. Dobra ilustracija ovog pristupa jeste kombinovana studija mutageneze i molekulskog dokinga koju su predstavili Chufan i saradnici [88].…”

Comparative docking and ADMET study of some curcumin derivatives and herbal congeners targeting β-amyloid

“…Normal range of log BB for brain/blood varies from -3.0 to 1.2 which was favorable for all the compounds except dibenzoyalmethane (-0.388). IC 50 represents the concentration of a drug that is required for 50 % inhibition in vitro (Pajeva et al 2009). LogHERG values for 95 % drugs are concern if it is less than -5.…”