Structure, solubility, and permeability relationships in a diverse middle molecule library

Hiroyuki Miyachi; Kayoko Kanamitsu; Mayumi Ishii; Eri Watanabe; Akira Katsuyama; Satoko Otsuguro; Fumika Yakushiji; Mizuki Watanabe; Kouhei Matsui; Yukina Sato; Satoshi Shuto; Takashi Tadokoro; Shunsuke Kita; Takanori Matsumaru; Akira Matsuda; Tomoyasu Hirose; Masato Iwatsuki; Yasuteru Shigeta; Tetsuo Nagano; Hirotatsu Kojima; Satoshi Ichikawa; Toshiaki Sunazuka; Katsumi Maenaka

doi:10.1016/j.bmcl.2021.127847

Structure, solubility, and permeability relationships in a diverse middle molecule library

Bioorg Med Chem Lett. 2021 Apr 1:37:127847. doi: 10.1016/j.bmcl.2021.127847. Epub 2021 Feb 9.

Authors

Hiroyuki Miyachi¹, Kayoko Kanamitsu², Mayumi Ishii², Eri Watanabe², Akira Katsuyama³, Satoko Otsuguro⁴, Fumika Yakushiji³, Mizuki Watanabe⁵, Kouhei Matsui⁵, Yukina Sato⁵, Satoshi Shuto⁵, Takashi Tadokoro⁵, Shunsuke Kita⁵, Takanori Matsumaru⁵, Akira Matsuda⁵, Tomoyasu Hirose⁶, Masato Iwatsuki⁶, Yasuteru Shigeta⁷, Tetsuo Nagano⁸, Hirotatsu Kojima⁸, Satoshi Ichikawa⁹, Toshiaki Sunazuka¹⁰, Katsumi Maenaka¹¹

Affiliations

¹ Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: miyachi_hiroyuki@mol.f.u-tokyo.ac.jp.
² Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
³ Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Science, Hokkaido University, Kita 12, Nishi 6, Kita ku, Sapporo 060 0812, Japan; Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
⁴ Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Science, Hokkaido University, Kita 12, Nishi 6, Kita ku, Sapporo 060 0812, Japan.
⁵ Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
⁶ Ōmura Satoshi Memorial Research Institute, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan.
⁷ Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
⁸ Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
⁹ Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Science, Hokkaido University, Kita 12, Nishi 6, Kita ku, Sapporo 060 0812, Japan; Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: ichikawa@pharm.hokudai.ac.jp.
¹⁰ Ōmura Satoshi Memorial Research Institute, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan. Electronic address: sunazukatoshiaki@yahoo.co.jp.
¹¹ Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Science, Hokkaido University, Kita 12, Nishi 6, Kita ku, Sapporo 060 0812, Japan; Global Station for Biosurfaces and Drug Discovery, Hokkaido University, Kita 12, Nishi 6, Kita ku, Sapporo 060 0812, Japan. Electronic address: maenaka@pharm.hokudai.ac.jp.

PMID: 33571648
DOI: 10.1016/j.bmcl.2021.127847

Abstract

To develop methodology to predict the potential druggability of middle molecules, we examined the structure, solubility, and permeability relationships of a diverse library (HKDL ver.1) consisting of 510 molecules (359 natural product derivatives, 76 non-natural products, 46 natural products, and 29 non-natural product derivatives). The library included peptides, depsipeptides, macrolides, and lignans, and 476 of the 510 compounds had a molecular weight in the range of 500-2000 Da. The solubility and passive diffusion velocity of the middle molecules were assessed using the parallel artificial membrane permeability assay (PAMPA). Quantitative values of solubility of 471 molecules and passive diffusion velocity of 287 molecules were obtained, and their correlations with the structural features of the molecules were examined. Based on the results, we propose a method to predict the passive diffusion characteristics of middle molecules from their three-dimensional structural features.

Keywords: HKDL ver.1; Middle molecule; Passive diffusion; Prediction; Solubility.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Diffusion
Membranes, Artificial
Molecular Structure
Permeability
Small Molecule Libraries / chemistry*
Solubility

Substances

Membranes, Artificial
Small Molecule Libraries