The objective of this proposal is the development of methods by which free energies of association of medicinal agents and biological molecules in water can be calculated. Having such methods will provide significantly improved procedures by which new medicinal agents can be designed. Central to the calculation of association free energies is the calculation of solvation energies in water. We will develop a continuum model for water which will provide estimates of solvation free energies rapidly and analytically. This model will provide a potential of mean force for the aqueous environment and be implemented as a standard energy term in a molecular mechanics force field. We will use the solvation model in a molecular dynamics-based full free energy simulation to evaluate enthalpies and entropies (and thus free energies) of association. Our initial calculations will be carried out on the antibiotic ristocetin which binds intermediates in bacterial cell wall biosynthesis. Experimental work will include measurements of solvation free energies for both small and large molecules, synthesis of conformationally restricted host molecules, and measurement of binding constants in water as tests of the theoretical methods to be developed. In connection with our studies of conformationally restricted molecules, we will develop a sequential constraint Monte Carlo conformational searching method which will be applicable to polymacrocycles and large, flexible molecules having many nOe-constrained internuclear distances.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044525-04
Application #
3303672
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1990-07-01
Project End
1994-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Other Domestic Higher Education
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027