Three- and four-body corrected fragment molecular orbital calculations with a novel subdividing fragmentation method applicable to structure-based drug design

Chiduru Watanabe, Kaori Fukuzawa, Yoshio Okiyama, Takayuki Tsukamoto, Akifumi Kato, Shigenori Tanaka, Yuji Mochizuki, Tatsuya Nakano

研究成果: Article査読

34 被引用数 (Scopus)

抄録

We develop an inter-fragment interaction energy (IFIE) analysis based on the three- and four-body corrected fragment molecular orbital (FMO3 and FMO4) method to evaluate the interactions of functional group units in structure-based drug design context. The novel subdividing fragmentation method for a ligand (in units of their functional groups) and amino acid residues (in units of their main and side chains) enables us to understand the ligand-binding mechanism in more detail without sacrificing chemical accuracy of the total energy and IFIEs by using the FMO4 method. We perform FMO4 calculations with the second order Møller-Plesset perturbation theory for an estrogen receptor (ER) and the 17β-estradiol (EST) complex using the proposed fragmentation method and assess the interaction for each ligand-binding site by the FMO4-IFIE analysis. When the steroidal EST is divided into two functional units including "A ring" and "D ring", respectively, the FMO4-IFIE analysis reveals their binding affinity with surrounding fragments of the amino acid residues; the "A ring" of EST has polarization interaction with the main chain of Thr347 and two hydrogen bonds with the side chains of Glu353 and Arg394; the "D ring" of EST has a hydrogen bond with the side chain of His524. In particular, the CH/π interactions of the "A ring" of EST with the side chains of Leu387 and Phe404 are easily identified in cooperation with the CHPI program. The FMO4-IFIE analysis using our novel subdividing fragmentation method, which provides higher resolution than the conventional IFIE analysis in units of ligand and each amino acid reside in the framework of two-body approximation, is a useful tool for revealing ligand-binding mechanism and would be applicable to rational drug design such as structure-based drug design and fragment-based drug design.

本文言語English
ページ(範囲)31-42
ページ数12
ジャーナルJournal of Molecular Graphics and Modelling
41
DOI
出版ステータスPublished - 2013 4月
外部発表はい

ASJC Scopus subject areas

  • 分光学
  • 物理化学および理論化学
  • コンピュータ グラフィックスおよびコンピュータ支援設計
  • 材料化学

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