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Discovery of a novel serine protease inhibitor utilizing a structure-based and experimental selection of fragments technique

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Abstract

We report a set of strategies to develop novel ligands (Structure Based and Experimental Selection of Fragments: SbE-SF). First, a docking simulation utilizing DOCK3.5 is performed in order to screen the fragment database, which was generated with the in-house program FRAGMENT++ specifically for docking simulation purposes. Although the affinity of these small molecules (fragments) is expected to be low, the affinity of fragments selected by computation is assayed by experiment to determine which ones can be potent inhibitors. After determining such key fragments, additional fragments are attached to the key ones in order to increase the binding affinity,taking into account the binding modes predicted by computation. This method has been applied to a thrombin inhibitor study, resulting in the discovery of a novel inhibitor exhibiting pIC50 = 7.9.

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Authors and Affiliations

  1. Pharmaceutical Research Laboratories, Ajinomoto Co., Inc, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, 210-8681, Japan

    Shingo Makino, Takashi Kayahara, Kazumi Tashiro, Mitsuo Takahashi, Takashi Tsuji & Masataka Shoji

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  1. Shingo Makino
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  2. Takashi Kayahara
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  3. Kazumi Tashiro
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  4. Mitsuo Takahashi
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  5. Takashi Tsuji
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  6. Masataka Shoji
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Makino, S., Kayahara, T., Tashiro, K. et al. Discovery of a novel serine protease inhibitor utilizing a structure-based and experimental selection of fragments technique. J Comput Aided Mol Des 15, 553–559 (2001). https://doi.org/10.1023/A:1011196407163

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