Novel Inhibitors of P‐Glycoprotein from In Silico Optimizations of Inhibitor SMU‐29 using the ChemGen Program

Abstract

P‐glycoprotein (P‐gp) is an integral membrane efflux pump that is capable of lowering the intracellular concentration of many drugs to sub‐therapeutic levels. Consequently, P‐gp has been implicated in multidrug resistances (MDR) to cancer chemotherapies. One promising P‐gp inhibitor, SMU‐29, was previously identified by us using in silico methods (Brewer et al., Molecular Pharmacology 86, 716–726, 2014) and was later confirmed to reverse MDR in cancer cell culture experiments (Follit et al., Pharmacol. Res. Perspect. 3, e00170, 2015). We created millions of SMU‐29 variants in silico using our novel medicinal chemistry program, ChemGen, in efforts to pharmacologically optimize SMU‐29. In one set of chemical variants, only part of the structure of SMU‐29 was varied; in a second set of variants, only the central structural scaffold of SMU‐29 was conserved. We used in silico docking to identify chemical variants of SMU‐29 that exhibited high estimated affinities for P‐gp's nucleotide binding domains (NBDs), and low estimated affinity for P‐gp's transmembrane drug‐binding domain (DBD). Using this approach, we identified over 2000 ChemGen‐created variants with equivalent or better estimated affinities at the P‐gp NBDs relative to SMU‐29. We selected a small set of these SMU‐29 variants for chemical synthesis and further screening in vitro against multidrug resistant cancer cell lines. All of the tested and synthesized SMU‐29 variants were observed to act as P‐gp inhibitors with improved PC50 values. Some of these variants were also observed to inhibit the breast cancer resistance protein (BCRP), a related ABC‐transporter that is also implicated in MDR in cancer. Our previous screens that identified SMU‐29 as a hit compound had a 33% P‐gp inhibitor identification success rate (hit rate); the present in silico optimization of SMU‐29 using ChemGen has demonstrated a very high success rate of identifying P‐gp inhibitors with improved affinities for the target protein.Support or Funding InformationThis work is supported by NIH NIGMS [R15GM094771‐02] to John G. Wise, SMU University Research Council, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and a private gift from Ms. Suzy Ruff of Dallas, Texas.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.