TY - JOUR
T1 - Structure, solubility, and permeability relationships in a diverse middle molecule library
AU - Miyachi, Hiroyuki
AU - Kanamitsu, Kayoko
AU - Ishii, Mayumi
AU - Watanabe, Eri
AU - Katsuyama, Akira
AU - Otsuguro, Satoko
AU - Yakushiji, Fumika
AU - Watanabe, Mizuki
AU - Matsui, Kouhei
AU - Sato, Yukina
AU - Shuto, Satoshi
AU - Tadokoro, Takashi
AU - Kita, Shunsuke
AU - Matsumaru, Takanori
AU - Matsuda, Akira
AU - Hirose, Tomoyasu
AU - Iwatsuki, Masato
AU - Shigeta, Yasuteru
AU - Nagano, Tetsuo
AU - Kojima, Hirotatsu
AU - Ichikawa, Satoshi
AU - Sunazuka, Toshiaki
AU - Maenaka, Katsumi
N1 - Funding Information:
This work was supported in part by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP20ae0101047h0001, and the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from the AMED under Grant Number JP20am0101087j0004. The authors gratefully thank the Drug Discover Initiative (DDI) at the University of Tokyo for providing the DDI library compounds. We thank Renee Mosi, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
KW - HKDL ver.1
KW - Middle molecule
KW - Passive diffusion
KW - Prediction
KW - Solubility
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U2 - 10.1016/j.bmcl.2021.127847
DO - 10.1016/j.bmcl.2021.127847
M3 - Article
C2 - 33571648
AN - SCOPUS:85101361424
SN - 0960-894X
VL - 37
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 127847
ER -