Design, synthesis and evaluation of progesterone–adenine hybrids as bivalent inhibitors of P-glycoprotein-mediated multidrug efflux

Synthesis of New Steroidal Inhibitors of P-Glycoprotein-Mediated Multidrug Resistance and Biological Evaluation on K562/R7 Erythroleukemia Cells

“…Fluorescence-quenching experiments have suggested interactions of steroid modulators in the proximity of the ATP-binding site , potentially associated with ATPase-dependent conformational changes controlling P-gp-mediated drug transport . Therefore, attempts have been made to generate P-gp inhibitors with mixed functions that are able to interfere with both ATPase and modulator sites. − The mechanisms underlying modulation of P-gp transport as well as ATPase activity appear complex owing to the involvement of several interacting binding sites according to ligand structures. − …”

Designing drugs and chemical probes with the dualsteric approach

“…In more cases, dualsteric modulators are designed by combining the orthosteric and allosteric ligand with a linker. 50,56,57,59,62,63,65,66,69,70,73,75,77–86,88,89,91,92,96,97,99,100,102–104,106–109,111,114–118,120–123,126,127,132,133,136,138,140,143,145,148–150,153,154,156,160,161,163,165,166,169,170,178–182,185,186,188,195,228 This is similar with the fragment-based drug discovery (FBDD). 229 The core fragments of drug binding is first identified and then the fragments are grown, merged, or linked into one complete molecule.…”

“…Other targets reported with dualsteric modulators include hydrolases, [163][164][165][166][167][168][169][170][171][172][173][174][175] isomerases, 176 oxidoreductases, 177,178 and transport proteins. [179][180][181][182][183][184][185][186][187][188] The small population of these cases suggests a broaden prospect for developing dualsteric modulators targeting proteins apart from GPCR and kinase.…”

“…A series of dualsteric peptide inhibitors have been discovered with improved potency. 168,[171][172][173][174] In transport proteins, Zeinyeh et al 179,180 developed inhibitors binding both the orthosteric and steroid binding site of P-glycoprotein, which shows better potency and selectivity. Dualsteric ligands targeting sodium channel was developed by conjugating its orthosteric and allosteric inhibitors with peptide linkers.…”

“…Dualsteric modulators, which bind to both orthosteric and allosteric sites, have been showing a good balance of potency and selectivity. 50,56,61–66,68,70,72,75,77–85,88,89,96–100,102,103,106,108,114,117,121–124,126,127,131,136,138,140,142–145,149,150,153,156,159–162,164–166,171–174,176,179–182,184–188,195–199 It could be found that the combined molecule would have a better selectivity than the orthosteric synthon while a better potency than the allosteric synthon. For example, Antony et al 136 designed a dualsteric modulator targeting muscarinic M 2 receptor (M 2 R).…”