Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores).

ABSTRACT: All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton-coupled folate transporter (PCFT) over the ubiquitously expressed reduced folate carrier (RFC). A lack of X-ray crystal structures or predictive models for PCFT or RFC has hindered structure-aided drug design for PCFT-selective therapeutics. Four-point validated models (pharmacophores) were generated for PCFT/Activity (HBA, NI, RA, RA) and RFC/Activity (HBD, NI, HBA, HBA) based on inhibition (IC50) of proliferation of isogenic Chinese hamster ovary (CHO) cells engineered to express only human PCFT or only RFC. Our

SUBMITTER: Shah K 

PROVIDER: S-EPMC5959037 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature