AUTHOR=Ivanenkov Yan A. , Zhavoronkov Alex , Yamidanov Renat S. , Osterman Ilya A. , Sergiev Petr V. , Aladinskiy Vladimir A. , Aladinskaya Anastasia V. , Terentiev Victor A. , Veselov Mark S. , Ayginin Andrey A. , Kartsev Victor G. , Skvortsov Dmitry A. , Chemeris Alexey V. , Baimiev Alexey Kh. , Sofronova Alina A. , Malyshev Alexander S. , Filkov Gleb I. , Bezrukov Dmitry S. , Zagribelnyy Bogdan A. , Putin Evgeny O. , Puchinina Maria M. , Dontsova Olga A. TITLE=Identification of Novel Antibacterials Using Machine Learning Techniques JOURNAL=Frontiers in Pharmacology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00913 DOI=10.3389/fphar.2019.00913 ISSN=1663-9812 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.