# MOLECULAR & ELECTRONIC STRUCTURES OF ANTIFOLATE

> **NIH NIH R01** · HAUPTMAN-WOODWARD MEDICAL RESEARCH INST · 1987 · $94,248

## Abstract

The primary objective of this research is to determine a
molecular level understanding of the biological mechanisms
regulating folate-dependent enzymes, in particular dihydrofolate
reductase (DHFR) and thymidylate synthase (TS).  A secondary
goal is to use this knowledge to facilitate the development of
folate-dependent enzyme inhibitors as more effective anticancer
drugs.  To elucidate correlations between structure and biological
activity, we will test our model relating antifolate potency and
conformationl flexibility using the antifolate structures available
in our data base to search for patterns of intra- and inter-
molecular interactions and hydrogen bond directionality and
compare these patterns with those observed for the enzyme-
inhibitor complexes.  Semiempirical molecular orbital and
molecular mechanics calculations of the energetic and entropic
ramification of these binding patterns will be carried out to assess
the role of solvent and electrostatic effects.  These goals  will be
achieved through (1) determination of the X-ray crystal structures
of selected members from four antifolate classes (lipophilic
diaminopyrimidines, soluble diamino s-triazines, lipophilic
quinazolines, and side chain modified antifolate pteridines), (2)
description of their molecular and electronic properties from
empirical molecular mechanics and ab initio molecular orbital
energy minimization techniques, and (3) testing of our models that
describe the specific binding interactions at the active site of the
enzyme-inhibitor complex.  This study will provide data that can
identify the stable conformational isomers of DHFR and TS
inhibitors, delineate their differing degrees of flexibility,
determine the influence of specific substituents upon
conformation, and define the nature of the active site
interactions in these inhibitors.  Although methotrexate is the
most widely used antifolate antineoplastic agent, its limitations
include poor cellular uptake, failure to cross the blood-brain
barrier and frequent occurrence of cell resistance.  In contrast,
lipophilic antifolates readily diffuse through cell membranes and
cross the blood-brain barrier.  However, their insolubility in
physiological media and their central nervous system toxicity are
major problems in their use.  The recent discovery that
polyglutamation of methotrexate enhances its cytotoxic action on
a number of folate-dependent enzymes, in particular TS, thereby
altering folate pools, suggests that polyglutamation plays an
important role in enzyme selectivity and specificity of action.
These factors further indicate that a detailed knowledge of these
antifolates at the molecular level is required to gain insight into
their mechanisms of action and to permit a more rational basis
for anticancer drug design.

## Key facts

- **NIH application ID:** 3172477
- **Project number:** 2R01CA034714-04
- **Recipient organization:** HAUPTMAN-WOODWARD MEDICAL RESEARCH INST
- **SAM.gov UEI:** HVQYC8JZB9A6
- **Principal Investigator:** Vivian Cody
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $94,248
- **Award type:** 2
- **Project period:** 1984-07-01 → 1992-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172477

## Citation

> US National Institutes of Health, RePORTER application 3172477, MOLECULAR & ELECTRONIC STRUCTURES OF ANTIFOLATE (2R01CA034714-04). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172477. Licensed CC0.

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