Molecular fields in quantitative structure–permeation relationships: the VolSurf approach

https://doi.org/10.1016/S0166-1280(99)00360-7Get rights and content

Abstract

Calculated molecular properties from 3D molecular fields of interaction energies have become a valuable approach to correlate 3D molecular structures with physicochemical and pharmacodynamic properties. In contrast, their use in correlations with pharmacokinetic properties is still poorly explored and exploited. 3D molecular fields can be obtained from ab initio, semiempirical or molecular mechanics levels of calculation. The newly developed procedure called VolSurf is able to compress the relevant information present in 3D maps into a few descriptors characterised by the simplicity of their use and interpretation. These descriptors can be quantitatively compared and used to build multivariate models correlating 3D molecular structures with biological responses. The VolSurf procedure is applied here to generate descriptors and models of structure–permeation relationships. The VolSurf procedure, which was originally designed to handle a medium amount of data, can easily be applied to problems of large size such as bioisostere databases, CombyChem databases and related approaches.

Introduction

Bioavailability, a term expressing the relative capacity of a drug to reach its site(s) of action from the site of administration, is often the bottleneck in drug optimisation. Bioavailability is related to a wealth of biological factors exemplified by membrane permeation, transport and biotransformation, which themselves depend heavily on molecular properties such as 3D structure, lipophilicity, H-bonding and the ratio between polar and apolar molecular surfaces. Hence, one can easily understand that bioavailability is a complex function of all these molecular properties.

To obtain useful descriptors accounting for partitioning and membrane transport is not an easy task. A large number of descriptors have been developed, all of which have major limitations in terms of relevance, interpretability or speed of calculation. Here, we present calculated molecular properties from 3D molecular fields of interaction energies as a novel approach to correlate 3D molecular structures with pharmacokinetic and physicochemical properties.

Section snippets

A brief survey of 3D molecular fields

A molecular field may be viewed as a 3D matrix, the elements of which (called grid nodes) are the attractive and repulsive forces, mapped by colour coding, between an interacting partner and a target (macro)molecule. The majority of properties related to molecular interactions can be represented in a 3D molecular field, hence its value in visualising large amounts of molecular data and chemical information in a simple and comprehensive manner.

A well-known example of a 3D molecular field is

The new VolSurf descriptors

3D molecular fields can be automatically converted into simpler molecular descriptors using a procedure called VolSurf [23]. The method is simple to apply and is specifically designed to produce descriptors related to pharmacokinetic properties, starting from 3D molecular field maps. In the standard procedure, interaction fields with a water probe and a hydrophobic probe are calculated all around the target molecules. However, other grid maps produced by different probes or by different

Physicochemical application of VolSurf descriptors

In order to demonstrate the physicochemical relevance of the VolSurf descriptors, we calculated the ΔG of hydration of 25 brassinosteroids using a semiempirical method [28], and correlated it with VolSurf descriptors. The calculations were carried out using AM1acqSM2 [28] as implemented in the SPARTAN program [29]. Each molecule was built in standard geometry and then energy-minimised. For the calculation of ΔG each molecular conformation was fully minimised in water. A water and a DRY probe

Conclusions

Calculated molecular properties from 3D molecular fields of interaction energies are a novel approach to correlate 3D molecular structures with pharmacodynamic, pharmacokinetic and physicochemical properties. The novel VolSurf descriptors quantitatively characterise size, shape, polarity, hydrophobicity and the balance between them. VolSurf descriptors are fast to calculate simple to interpret and independent of the alignment of molecules. VolSurf descriptors are relatively independent of

Acknowledgements

We are grateful to W. Guba (Hoechst Marion Roussel, Germany), M. Pastor (Multivariate Infometrics Analysis, Perugia, Italy) and S. Clementi (Laboratory for Chemometrics, Perugia, Italy) for their help and valuable discussions, and to I. Zamora for making available the brassinosteroid structures used in the hydration example. B.T. and P.A.C. acknowledge support by the Swiss National Science Foundation.

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