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Content archived on 2024-06-18

Calculation of Pharmacokinetic Properties of Druglike Molecules using Integral Equation Theory

Objective

"Accurate calculation of the hydration free energies of organic molecules is a long-standing challenge in computational chemistry and is important in many aspects of research in the pharmaceutical and agrochemical industries. For example, many of the pharmacokinetic properties of potential drug molecules are defined by their in vivo solvation and acid-base behavior, which can be estimated from their hydration free energies.

Commonly used methods to calculate hydration free energy (e.g. continuum solvent models and explicit solvent simulations) are either too inaccurate or too computationally expensive for routine use in the pharmaceutical industry. In a recent blind test for the calculation of hydration free energies of druglike molecules using existing methods, the best predictions were in the range RMSE = 2.5 – 3.5 kcal/mol, which equates to a ~2 log unit error in the related pharmacokinetic property (estimated from G(solv) = −RT ln K). [Guthrie, J.P. J. Phys. Chem. B, 2009, 113, 4501]

Integral equation theory (IET) is an alternative framework for the calculation of hydration free energies. IET retains information about the solvent structure (in the form of density correlation functions), but estimates the solute chemical potential without the need for long explicit solvent simulations. In a recent proof-of-concept study, Palmer (the “experienced researcher”) and Fedorov (the “scientist in charge”) demonstrated that using IET it is possible to calculate hydration free energies of druglike molecules more accurately than with other existing methods (RMSE for a test set of 19 molecules was less than 1.2 kcal/mol). [Palmer, D.S. et al. J. Chem. Phys., 2010, 133, 044104]

The purpose of this proposal is to build upon earlier work and to develop real-world tools for predicting the pharmacokinetic properties of druglike molecules using IET."

Topic(s)

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Call for proposal

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FP7-PEOPLE-2010-IEF
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Funding Scheme

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MC-IEF - Intra-European Fellowships (IEF)

Coordinator

UNIVERSITY OF STRATHCLYDE
EU contribution
€ 192 849,60
Address
Richmond Street 16
G1 1XQ Glasgow
United Kingdom

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Activity type
Higher or Secondary Education Establishments
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Total cost

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