Laboratory of Molecular Design is engaged in developing software for drug screening and design. We also perform organic synthesis of the designed compound and evaluate the potency of the synthesized molecule. Our present targets are viral and bacterial proteins. The cancer-related molecules are also our keen interest. Not only compounds but also highly specific antibodies is our scope for the rational molecular design.
The binding structure between a compound and its target protein is critical information for drug discovery and development. The growth of the high-quality single crystal is important for X-ray structure analysis. We perform X-ray crystallography and electron microscopy for our target proteins. A significant concern is why the preferences for precipitants differ among proteins.1-3 Our computational and experimental studies suggest that the shape of electrostatic potential is responsible for the molecular arrangement.4,5 We currently investigate the role of the glycan agents in protein crystal growth with ammonium sulfate.
 Qi, F. et al. J. Chem. Inf. Model. 2015, 55, 1673−1685
 Fudo, S. et al. Cryst. Growth Des. 2017, 17 (2), 534-542
 Kitahara, M. et al. Cryst. Growth Des. 2019, 19 (11), 6004-6010
 Guo, Y. et al. Cryst. Growth Des. 2021, 21 (1), 297–305
 Guo, Y. et al. J. Chem. Inf. Model. 2021, 61 (9), 4571–4581
Finding a hit molecule to a disease-related target is the first step of drug discovery. We are engaged in the massive computational screening by the World Community Grid project. Several potent compounds have been identified in the project, and the modifications are carried out for the hit compounds. Our keen interest is an immunoglobulin, which is the central molecule of antibody drugs. Our computational analysis is helpful in enhancing the stability of the antibody scFv form,6 which results in the increases of the expression level of the recombinant scFv in bacterial production. We have performed computational analysis on the binding modes of antigen-antibody complexes,7 and the molecular interaction in the antibody recognition of antigen.8 We are currently developing a computer program for fully automated maturation of immunoglobulin molecules for a target antigen.
 Hoshino, T. et al. Asia-Pac. BioTech News. 2016, 20, 32-34
 Qiao, X. et al. J. Phys. Chem. B. 2021, 125 (41), 11374–11385
 Qu, L. et al. J. Chem. Inf. Model. 2021, 61 (5), 2396–2406
We have developed a software program, Hydrophobe, to predict the binding site and the binding mode of ligands to a target protein for structure-based drug design (SBDD).9 We have also developed a software program, Orientation, that enables the evaluation of binding affinity and geometry optimization.10 We currently apply image processing and machine learning techniques to analysis molecular interaction.
 Fuji, H. et al. e-J. Surf. Sci. Nanotech. 2008, 6, 241–245.
 Fuji, H. et al. Chem. Pharm. Bull. 2017, 65 (5), 461–468.
We apply the computational tools for the discovery of agents of cancer therapy. We have developed small chemical compounds targeting the BDNF-binding domain of TrkB.11 We are also engaged in the study of the far-upstream element-binding protein-interacting repressor (FIR) and its exon2-lacking variant (FIRΔexon2). FIRΔexon2 is a significant target for cancer therapy. FIRΔexon2 or autoantibody for FIRΔexon2 will be a potent biomarker for detecting the early stage of gastric and other kinds of cancers.12,13
 Nakamura, Y. et al. Cancer Med. 2014, 3 (1), 25-35
 Ailiken, G. et al. Oncogenesis 2020, 9, 26
 Kobayashi, S. et al. Cancer Sci. 2021, 7 (4), 826-837
Multidrug-resistant (MDR) bacterial infections are a severe threat to public health. β-lactamase is a significant target of antibiotics. We have identified inhibitory compounds for metallo-β-lactamases.14 Influenza virus is one of the hazardous viruses to humans, and the development of new antiviral agents is still demanded to prepare for a global pandemic. We investigate endonuclease inhibitors aiming at hemagglutinin15 and viral polymerase acidic protein N-terminal domain (PAN).16,17 It is hard to effect a radical cure for human immunodeficiency virus type 1 (HIV-1) infectious diseases. We have examined the mechanism of drug resistance of HIV-1 and developed inhibitory compounds for HIV-1 RNase H activity. 18-20
 Kamo, T. et al. Chem. Pharm. Bull. 2021, 69 (12), 1179–1183
 Yanagita, H. et al. ACS Chem. Biol. 2012, 7 (3), 552-562
 Fudo, S. et al. Bioorg. Med. Chem. 2015, 23 (17), 5466–5475
 Fudo, S. et al. Biochemistry 2016, 55 (18), 2646–2660
 Fuji, H. et al. J. Med. Chem. 2009, 52 (5), 1380-1387
 Yanagita, H. et al. Bioorg. Med. Chem. 2011, 19 (2), 816-825
 Yanagita, H. et al. Chem. Pharm. Bull. 2012, 60 (6), 764-771
Email: hoshino [at] chiba-u.jp