# Exploiting Solvation Structure and Thermodynamics for Prospective Drug Discovery and Rational Design

> **NIH NIH SC3** · HERBERT H. LEHMAN COLLEGE · 2020 · $123,750

## Abstract

The displacement of water from a protein surface upon the binding of a drug has a significant, if
not dominant, contribution to the free energy of recognition, and hence plays a significant role
in determining drug potency and specificity. Despite the importance of water in mediating drug-
protein interactions, commonly used structure-based models do not explicitly treat water as a
molecule. Instead, they indirectly hydration effects by categorizing ligand-protein contacts as
either hydrophobic or hydrophilic or by modeling water as a continuum. Neither of these
approaches accounts for the finite size and directed nature of water's hydrogen bonds, the
physics of which is essential for describing the hydration of the diverse environment of confined
protein binding sites. The adoption of simplified treatments of water in drug design applications
has been made necessary by the complexity of hydration phenomena and the lack of a
molecular-based framework for its structural and thermodynamic analysis. In recent years, the
PI has been instrumental in developing two methodologies that utilize inhomogeneous fluid
solvation theory (IST) to map out solvation structural and thermodynamic properties of water in
molecular detail in protein binding sites: 1) A hydration site analysis (HSA) approach, which
forms the basis for Schrodinger LLC's WaterMap and 2) A corresponding high-resolution grid-
based implementation, GIST, now available in the freely distributed AmberTools. Each of these
analysis tools maps out 24 independent measures of structure and thermodynamics.
In this proposal we will incorporate solvation structure and thermodynamic maps into virtual
screening and lead optimization methodologies to improve our ability to identify and design
compounds that bind with high affinity and specificity to a targeted member of a family of
proteins. We propose to optimize and apply these methods to two important drug targets: the
dopamine receptor D3, a target for the treatment of drug addiction, and the μ-OR opioid
receptor, an important target for pain alleviation. We have chosen these receptors because of the
challenges of targeting them specifically. Off-target binding often results in either the inability
to discover viable drugs (D3) or drugs which have significant undesirable side effects (μ -OR).
Current methodologies have been ineffective in finding specific binders for these targets. Hence
they remain drug targets of significant interest in both academic and industrial settings and the
natural choice for the application of the new discovery methodologies proposed here.

## Key facts

- **NIH application ID:** 9853799
- **Project number:** 5SC3GM095417-08
- **Recipient organization:** HERBERT H. LEHMAN COLLEGE
- **Principal Investigator:** Thomas Philip Kurtzman
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $123,750
- **Award type:** 5
- **Project period:** 2012-04-10 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853799

## Citation

> US National Institutes of Health, RePORTER application 9853799, Exploiting Solvation Structure and Thermodynamics for Prospective Drug Discovery and Rational Design (5SC3GM095417-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9853799. Licensed CC0.

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