Project Details


The primary goal of this research is to attain a molecular level
understanding of the biophysical mechanisms regulating folate-
dependent enzymes, in particular dihydrofolate reductase (DHFR).
A secondary goal is to use this understanding to facilitate the
development of folate-dependent enzyme inhibitors as more
effective anticancer drugs. For elucidating correlations between
molecular structure and bioactivity, a database of over 100
antifolate X-ray crystal structures will be used to search for
patterns of intra- and inter-molecular interactions and to test a
working model relating high antifolate potency and low
conformational flexibility. These patterns will be compared with
those observed for the enzyme-inhibitor complexes to determine
their prevalence in various environments. Computational
chemistry techniques, including empirical force-field and
molecular orbital calculations along with molecular computer
graphics, will be employed to assess the energetic and entropic
ramifications of these binding patterns and the role of solvent and
electrostatic effects. Our specific focus will be on selected
members from four antifolate classes, representatives of which
are available from the antifolate structural database. Regarding
these specified substrates and inhibitors of DHFR, our research
plan is (1) to characterize their conformational profile in terms of
conformational energy and entropy, preferred conformers,
rotational barriers, and overall thermodynamic and dynamic
flexibility; (2) to explore the influence of substituents,
protonation and solvent on these conformational features; (3) to
delineate correlations between molecular structure and
conformation on the one hand and antifolate activity on the other,
and (4) To initiate a theoretical probe of the specific binding
interactions involved in formation of the DHFR-inhibitor
complex. It is well known but less well understood that small
changes in molecular structure often give rise to large variations
in antifolate activity. Hence the proposed studies are aimed at a
systematic and detailed theoretical analysis of the role of
structure and conformation in dictating bioactivity, thus
permitting a more rational basis for anticancer drug design.
Effective start/end date5/1/889/30/90


  • National Institutes of Health


  • Medicine(all)

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