IETSOL

Calculation of Pharmacokinetic Properties of Druglike Molecules using Integral Equation Theory

Coordinatore	UNIVERSITY OF STRATHCLYDE    more  Organization address address: Richmond Street 16 city: GLASGOW postcode: G1 1XQ contact info Titolo: Mr. Nome: Martin Cognome: Gregory Email: send email Telefono: +44 141 548 2524 Fax: +44 141 552 4409
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	192˙849 €
EC contributo	192˙849 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2010-IEF
Funding Scheme	MC-IEF
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-02-01   -   2014-01-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITY OF STRATHCLYDE  Organization address address: Richmond Street 16 city: GLASGOW postcode: G1 1XQ contact info Titolo: Mr. Nome: Martin Cognome: Gregory Email: send email Telefono: +44 141 548 2524 Fax: +44 141 552 4409	UK (GLASGOW)	coordinator	192˙849.60

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 Obiettivo del progetto (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.'