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J Comput Aided Mol Des. 2018 Nov;32(11):1229-1245. doi: 10.1007/s10822-018-0160-8. Epub 2018 Sep 8.

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

Author information

1
Department of Pharmaceutical Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. yamaotsun@pharm.kitasato-u.ac.jp.
2
Department of Pharmaceutical Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. hironos@pharm.kitasato-u.ac.jp.

Abstract

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.

KEYWORDS:

Fragment growing; Fragment mapping; Fragment-based drug discovery; Virtual screening

PMID:
30196523
DOI:
10.1007/s10822-018-0160-8

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