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VISCANA: Visualized Cluster Analysis of Protein−Ligand Interaction Based on the ab Initio Fragment Molecular Orbital Method for Virtual Ligand Screening

Supporting Info

Shinji Amari,*^†^‡ Masahiro Aizawa,^†^‡ Junwei Zhang,^†^‡ Kaori Fukuzawa,^§ Yuji Mochizuki,^†^‡ Yoshio Iwasawa,^‡ Kotoko Nakata,^‡ Hiroshi Chuman, and Tatsuya Nakano^†^‡^#

Collaborative Research Center of Frontier Simulation Software for Industrial Science, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan, Revolutionary Simulation Software (RSS21) Project, Collaborative Research Center of Frontier Simulation Software for Industrial Science, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan, Mizuho Information & Research Institute, Inc., 2-3 Kanda-Nishikicho, Chiyoda-ku, Tokyo 101-8443, Japan, AdvanceSoft Corporation, Center for Collaborative Research, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan, Institute of Health Biosciences, University of Tokushima, 1-78-1 Shoumachi, Tokushima 770-8505, Japan, and Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan

J. Chem. Inf. Model., 2006, 46 (1), pp 221–230

DOI: 10.1021/ci050262q

Publication Date (Web): November 12, 2005

Corresponding author phone: +81-3-5452-6622; fax: +81-3-5452-6623; e-mail: samari@fsis.iis.u-tokyo.ac.jp.

†

Institute of Industrial Science, University of Tokyo.

‡

Revolutionary Simulation Software Project.

Mizuho Information & Research Institute, Inc.

AdvanceSoft Corporation.

University of Tokushima.

National Institute of Health Sciences.

Abstract

We have developed a visualized cluster analysis of protein−ligand interaction (VISCANA) that analyzes the pattern of the interaction of the receptor and ligand on the basis of quantum theory for virtual ligand screening. Kitaura et al. (Chem. Phys. Lett. 1999, 312, 319−324.) have proposed an ab initio fragment molecular orbital (FMO) method by which large molecules such as proteins can be easily treated with chemical accuracy. In the FMO method, a total energy of the molecule is evaluated by summation of fragment energies and interfragment interaction energies (IFIEs). In this paper, we have proposed a cluster analysis using the dissimilarity that is defined as the squared Euclidean distance between IFIEs of two ligands. Although the result of an ordered table by clustering is still a massive collection of numbers, we combine a clustering method with a graphical representation of the IFIEs by representing each data point with colors that quantitatively and qualitatively reflect the IFIEs. We applied VISCANA to a docking study of pharmacophores of the human estrogen receptor α ligand-binding domain (57 amino acid residues). By using VISCANA, we could classify even structurally different ligands into functionally similar clusters according to the interaction pattern of a ligand and amino acid residues of the receptor protein. In addition, VISCANA could estimate the correct docking conformation by analyzing patterns of the receptor−ligand interactions of some conformations through the docking calculation.

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