Journal of Computer-Aided Molecular Design

, Volume 32, Issue 11, pp 1229–1245 | Cite as

In silico fragment-mapping method: a new tool for fragment-based/structure-based drug discovery

  • Noriyuki YamaotsuEmail author
  • Shuichi HironoEmail author


Here, we propose an in silico fragment-mapping method as a potential tool for fragment-based/structure-based drug discovery (FBDD/SBDD). For this method, we created a database named Canonical Subsite–Fragment DataBase (CSFDB) and developed a knowledge-based fragment-mapping program, Fsubsite. CSFDB consists of various pairs of subsite–fragments derived from X-ray crystal structures of known protein–ligand complexes. Using three-dimensional similarity-matching between subsites on one protein and another, Fsubsite compares the surface of a target protein with all subsites in CSFDB. When a local topography similar to the subsite is found on the surface, Fsubsite places a fragment combined with the subsite in CSFDB on the target protein. For validation purposes, we applied the method to the apo-structure of cyclin-dependent kinase 2 (CDK2) and identified four compounds containing three mapped fragments that existed in the list of known inhibitors of CDK2. Next, the utility of our fragment-mapping method for fragment-growing was examined on the complex structure of tRNA-guanine transglycosylase with a small ligand. Fsubsite mapped appropriate fragments on the same position as the binding ligand or in the vicinity of the ligand. Finally, a 3D-pharmacophore model was constructed from the fragments mapped on the apo-structure of heat shock protein 90-α (HSP90α). Then, 3D pharmacophore-based virtual screening was carried out using a commercially available compound database. The resultant hit compounds were very similar to a known ligand of HSP90α. As a result of these findings, this in silico fragment-mapping method seems to be a useful tool for computational FBDD and SBDD.


Fragment mapping Fragment-based drug discovery Fragment growing Virtual screening 



This work was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP15K07899. We would like to thank Dr. Hiroyuki Yamasaki and Dr. Yoshihiko Nishibata (Pharmaceutical Informatics, School of Pharmacy, Kitasato University) for providing the FAS program.

Supplementary material

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Supplementary material 1 (DOCX 920 KB)
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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of PharmacyKitasato UniversityTokyoJapan

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