This project seeks to develop a rational design methodology that utilizes a powerful solvation analysis tool, WaterMap, to direct the modification of lead compounds so that they bind with greater affinity to a given target. The methodology will be applied to design modifications to flavonoid compounds so that the resulting analogues specifically and strongly inhibit members of the Caspase family of proteins. The WaterMap technology utilizes explicit molecular dynamics simulations and a rigorous statistical mechanical theoretical treatment to create an approximate 3-dimensional mapping of the chemical potential of solvation of protein active sites. This methodology addresses two well-known deficiencies in most computational methods aimed at predicting ligand-binding affinity. First, while maintaining computational efficiency, it captures essential molecular length scale physics of water solvation that most methodologies aimed at predicting ligand-protein binding affinities ignore. Second, it provides specific information and physical insight into how lead-drugs should be modified such as to produce derivatives that can bind with greater affinity and with specificity to given targets Because of these features, the WaterMap methodology shows great promise as an aid in the lead optimization process. The rational design of flavonoid analogues that are more specific and stronger inhibitors of the caspase family of proteins will serve as a test case with the long term goal of developing a methodology that is applicable to all hydrated protein targets.
Specific Aim 1 seeks to design and implement a rational design methodology that incorporates solvation information provided by the WaterMap technology that is capable of directing the design of modifications to lead compounds such that they bind with higher affinity to given targets. The assessment of Specific Aim 1 will be the goal of Specific Aim 2 which is to apply the new methodology to design modifications to flavonoid compounds that result in flavonoid analogues that bind with greater affinity to members of the Caspase family of proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM095417-02
Application #
8458118
Study Section
Special Emphasis Panel (ZGM1-MBRS-1 (SC))
Program Officer
Okita, Richard T
Project Start
2012-04-10
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$117,971
Indirect Cost
$45,596
Name
Herbert H. Lehman College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
620128301
City
New York
State
NY
Country
United States
Zip Code
10468
Nguyen, Crystal N; Cruz, Anthony; Gilson, Michael K et al. (2014) Thermodynamics of Water in an Enzyme Active Site: Grid-Based Hydration Analysis of Coagulation Factor Xa. J Chem Theory Comput 10:2769-2780