Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based on SVM Model, Pharmacophore, and Molecular Docking

• Published in: Journal of chemical information and modeling 2011-06, Vol.51 (6), p.1364-1375
• Main Authors: Ren, Ji-Xia, Li, Lin-Li, Zheng, Ren-Lin, Xie, Huan-Zhang, Cao, Zhi-Xing, Feng, Shan, Pan, You-Li, Chen, Xin, Wei, Yu-Quan, Yang, Sheng-Yong
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Analytical chemistry; Applied sciences; Artificial Intelligence; Biological and medical sciences; Chemical compounds; Chemistry; Computer science; control theory; systems; Data processing. List processing. Character string processing; Drug Evaluation, Preclinical - methods; Exact sciences and technology; General and physical chemistry; General pharmacology; General. Nomenclature, chemical documentation, computer chemistry; Kinases; Medical sciences; Memory organisation. Data processing; Models, Molecular; Molecular structure; Pharmaceutical Modeling; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Protein Conformation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - chemistry; Proto-Oncogene Proteins c-pim-1 - metabolism; Reproducibility of Results; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacology; Software; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry; Time Factors; User-Computer Interface
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci100464b

In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors.