Frontiers in Pharmacology (Aug 2019)
Identification of Novel Antibacterials Using Machine Learning Techniques
- Yan A. Ivanenkov,
- Yan A. Ivanenkov,
- Yan A. Ivanenkov,
- Yan A. Ivanenkov,
- Alex Zhavoronkov,
- Renat S. Yamidanov,
- Renat S. Yamidanov,
- Ilya A. Osterman,
- Ilya A. Osterman,
- Petr V. Sergiev,
- Petr V. Sergiev,
- Vladimir A. Aladinskiy,
- Vladimir A. Aladinskiy,
- Anastasia V. Aladinskaya,
- Anastasia V. Aladinskaya,
- Victor A. Terentiev,
- Victor A. Terentiev,
- Victor A. Terentiev,
- Mark S. Veselov,
- Mark S. Veselov,
- Mark S. Veselov,
- Andrey A. Ayginin,
- Andrey A. Ayginin,
- Victor G. Kartsev,
- Dmitry A. Skvortsov,
- Dmitry A. Skvortsov,
- Alexey V. Chemeris,
- Alexey Kh. Baimiev,
- Alina A. Sofronova,
- Alexander S. Malyshev,
- Gleb I. Filkov,
- Dmitry S. Bezrukov,
- Dmitry S. Bezrukov,
- Bogdan A. Zagribelnyy,
- Evgeny O. Putin,
- Maria M. Puchinina,
- Olga A. Dontsova,
- Olga A. Dontsova,
- Olga A. Dontsova
Affiliations
- Yan A. Ivanenkov
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia
- Yan A. Ivanenkov
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
- Yan A. Ivanenkov
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
- Yan A. Ivanenkov
- Insilico Medicine, Inc. Johns Hopkins University, Rockville, MD, United States
- Alex Zhavoronkov
- Insilico Medicine, Inc. Johns Hopkins University, Rockville, MD, United States
- Renat S. Yamidanov
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia
- Renat S. Yamidanov
- Insilico Medicine, Inc. Johns Hopkins University, Rockville, MD, United States
- Ilya A. Osterman
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
- Ilya A. Osterman
- Skolkovo Institute of Science and Technology, Skolkovo, Russia
- Petr V. Sergiev
- Skolkovo Institute of Science and Technology, Skolkovo, Russia
- Petr V. Sergiev
- Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
- Vladimir A. Aladinskiy
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
- Vladimir A. Aladinskiy
- Insilico Medicine, Inc. Johns Hopkins University, Rockville, MD, United States
- Anastasia V. Aladinskaya
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
- Anastasia V. Aladinskaya
- Insilico Medicine, Inc. Johns Hopkins University, Rockville, MD, United States
- Victor A. Terentiev
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia
- Victor A. Terentiev
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
- Victor A. Terentiev
- Insilico Medicine, Inc. Johns Hopkins University, Rockville, MD, United States
- Mark S. Veselov
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia
- Mark S. Veselov
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
- Mark S. Veselov
- Insilico Medicine, Inc. Johns Hopkins University, Rockville, MD, United States
- Andrey A. Ayginin
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia
- Andrey A. Ayginin
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
- Victor G. Kartsev
- InterBioScreen ltd, Chernogolovka, Russia
- Dmitry A. Skvortsov
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
- Dmitry A. Skvortsov
- Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia
- Alexey V. Chemeris
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia
- Alexey Kh. Baimiev
- Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS) Ufa Scientific Centre, Ufa, Russia
- Alina A. Sofronova
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
- Alexander S. Malyshev
- 0Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
- Gleb I. Filkov
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
- Dmitry S. Bezrukov
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
- Dmitry S. Bezrukov
- Skolkovo Institute of Science and Technology, Skolkovo, Russia
- Bogdan A. Zagribelnyy
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
- Evgeny O. Putin
- 1Computer Technologies Lab, ITMO University, St. Petersburg, Russia
- Maria M. Puchinina
- Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
- Olga A. Dontsova
- Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
- Olga A. Dontsova
- Skolkovo Institute of Science and Technology, Skolkovo, Russia
- Olga A. Dontsova
- Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
- DOI
- https://doi.org/10.3389/fphar.2019.00913
- Journal volume & issue
-
Vol. 10
Abstract
Many pharmaceutical companies are avoiding the development of novel antibacterials due to a range of rational reasons and the high risk of failure. However, there is an urgent need for novel antibiotics especially against resistant bacterial strains. Available in silico models suffer from many drawbacks and, therefore, are not applicable for scoring novel molecules with high structural diversity by their antibacterial potency. Considering this, the overall aim of this study was to develop an efficient in silico model able to find compounds that have plenty of chances to exhibit antibacterial activity. Based on a proprietary screening campaign, we have accumulated a representative dataset of more than 140,000 molecules with antibacterial activity against Escherichia coli assessed in the same assay and under the same conditions. This intriguing set has no analogue in the scientific literature. We applied six in silico techniques to mine these data. For external validation, we used 5,000 compounds with low similarity towards training samples. The antibacterial activity of the selected molecules against E. coli was assessed using a comprehensive biological study. Kohonen-based nonlinear mapping was used for the first time and provided the best predictive power (av. 75.5%). Several compounds showed an outstanding antibacterial potency and were identified as translation machinery inhibitors in vitro and in vivo. For the best compounds, MIC and CC50 values were determined to allow us to estimate a selectivity index (SI). Many active compounds have a robust IP position.
Keywords
- novel antibacterials
- machine learning techniques
- translation inhibitors
- virtual screening
- Kohonen-based SOM
