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Molecular Interaction Fields (MIFs) to Predict Lipophilicity and ADME Profile of Antitumor Pt(II) Complexes

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ABSTRACT

Purpose

To describe a computational tool to calculate molecular descriptors of potential application in ADME virtual screening of antitumor Pt(II) drug candidates.

Methods

The multistep computational procedure consists in (a) building and optimization (PM3) of the 3D structures of the investigated complexes, (b) parametrization of Pt(II) and its implementation in GRID, (c) GRID calculations and extraction of the information content with VolSurf and BIOCUBE4mf, and (d) PLS analysis to look for the correlation between experimental data and the molecular descriptors.

Results

The following results were obtained: (a) the calibration of the GRID force field to take into account the platinum di-cation, (b) solid PLS models between log k30 and log kw with VolSurf descriptors which highlight the main structural differences between the two chromatographic parameters, (c) the prediction of virtual (of each conformer) log k30 and log kw, and (d) the identification of the main descriptors governing VDss of drugs in clinical use.

Conclusion

The study suggests a strategy to identify good Pt(II) complexes prior to their synthesis to eliminate as soon as possible drug candidates with unfavorable PK profile.

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Authors and Affiliations

  1. CASSMedChem Research Group, DSTF at the Centre for Innovation, Università di Torino, Via Quarello 11, 10135, Torino, Italy

    Giulia Caron & Giuseppe Ermondi

  2. Dipartimento di Scienze dell’Ambiente e della Vita, Università del Piemonte Orientale “Amedeo Avogadro”, Viale Michel 11, 15121, Alessandria, Italy

    Mauro Ravera

Authors
  1. Giulia Caron
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  2. Mauro Ravera
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  3. Giuseppe Ermondi
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Corresponding author

Correspondence to Giuseppe Ermondi.

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ESM 1

Supporting Information: Chemical structures and experimental lipophilicity indexes, VIPs and PLS coefficients; VolSurf descriptors definitions; X-ray structures used for building models. (DOC 553 kb)

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Caron, G., Ravera, M. & Ermondi, G. Molecular Interaction Fields (MIFs) to Predict Lipophilicity and ADME Profile of Antitumor Pt(II) Complexes. Pharm Res 28, 640–646 (2011). https://doi.org/10.1007/s11095-010-0317-1

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  • DOI: https://doi.org/10.1007/s11095-010-0317-1

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