A QM/MM study of the binding of RAPTA ligands to cathepsin B

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• 作者：Antonella Ciancetta (1)
  Samuel Genheden (2)
  Ulf Ryde (2) ulf.ryde@teokem.lu.se
• 关键词：QM/MM – ; Ligand ; binding affinities – ; Ruthenium – ; Anticancer drugs – ; Cathepsin B – ; Continuum solvation – ; QM/MM ; PBSA
• 刊名：Journal of Computer-Aided Molecular Design
• 出版年：2011
• 出版时间：August 2011
• 年：2011
• 卷：25
• 期：8
• 页码：729-742
• 全文大小：1.9 MB
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• 作者单位：1. Dipartimento di Scienze del Farmaco, Universit脿 degli Studi 鈥淕. D鈥橝nnunzio鈥?Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy2. Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124, 221 00 Lund, Sweden
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Physical Chemistry
  Computer Applications in Chemistry
  Animal Anatomy, Morphology and Histology
  
• 出版者：Springer Netherlands
• ISSN：1573-4951

文摘

We have carried out quantum mechanical (QM) and QM/MM (combined QM and molecular mechanics) calculations, as well as molecular dynamics (MD) simulations to study the binding of a series of six RAPTA (Ru(II)-arene-1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane) complexes with different arene substituents to cathepsin B. The recently developed QM/MM-PBSA approach (QM/MM combined with Poisson–Boltzmann solvent-accessible surface area solvation) has been used to estimate binding affinities. The QM calculations reproduce the antitumour activities of the complexes with a correlation coefficient (r 2) of 0.35–0.86 after a conformational search. The QM/MM-PBSA method gave a better correlation (r 2 = 0.59) when the protein was fixed to the crystal structure, but more reasonable ligand structures and absolute binding energies were obtained if the protein was allowed to relax, indicating that the ligands are strained when the protein is kept fixed. In addition, the best correlation (r 2 = 0.80) was obtained when only the QM energies were used, which suggests that the MM and continuum solvation energies are not accurate enough to predict the binding of a charged metal complex to a charged protein. Taking into account the protein flexibility by means of MD simulations slightly improves the correlation (r 2 = 0.91), but the absolute energies are still too large and the results are sensitive to the details in the calculations, illustrating that it is hard to obtain stable predictions when full flexible protein is included in the calculations.