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Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate

Khushbu Shah1, Sudhir Raghavan1, Zhanjun Hou2

  • 1Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.

Journal of Molecular Graphics & Modelling
|March 19, 2018
PubMed

Insights

Novel antifolates aim for tumor-specific delivery by targeting the proton-coupled folate transporter (PCFT) over the reduced folate carrier (RFC). This study developed predictive models to guide the design of selective cancer therapeutics, minimizing side effects.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Drug Discovery

Background:

  • Clinically used antifolates lack tumor selectivity, leading to dose-limiting toxicities.
  • Targeting the proton-coupled folate transporter (PCFT) offers a strategy for tumor-selective antifolate delivery over the reduced folate carrier (RFC).
  • Lack of structural data for PCFT and RFC impedes structure-based drug design for selective antifolates.

Purpose of the Study:

  • To develop validated pharmacophore models for PCFT and RFC to enable structure-aided design of novel antifolates.
  • To identify key structural differences in molecule recognition between PCFT and RFC.
  • To facilitate the development of tumor-targeted cytotoxic antifolates with improved selectivity.

Main Methods:

  • Generated four-point pharmacophore models for PCFT and RFC based on inhibition data (IC50) of cell proliferation.
  • Utilized isogenic Chinese hamster ovary (CHO) cells engineered to express either human PCFT or RFC.
  • Analyzed distinct structural features required for transporter recognition and activity.

Main Results:

  • Developed distinct pharmacophore models: PCFT/Activity (HBA, NI, RA, RA) and RFC/Activity (HBD, NI, HBA, HBA).
  • Revealed significant differences in the structural requirements for substrate transport by PCFT and RFC.
  • Demonstrated the potential for exploiting these differences to design transporter-selective antifolates.

Conclusions:

  • The developed pharmacophore models provide a basis for structure-based drug design of PCFT-selective antifolates.
  • Understanding transporter-specific structural features is crucial for developing targeted cancer therapies.
  • This work paves the way for novel antifolate drugs with enhanced tumor selectivity and reduced systemic toxicity.

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