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

Citations Over TimeTop 10% of 2011 papers

Abstract

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.

Related Papers

• → Developing a Naïve Bayesian Classification Model with PI3Kγ structural features for virtual screening against PI3Kγ: Combining molecular docking and pharmacophore based on multiple PI3Kγ conformations(2022)25 cited
• → Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model(2019)24 cited
• → Discovery of potential ZAP-70 kinase inhibitors: Pharmacophore design, database screening and docking studies(2009)13 cited
• → Identification of Anti‐Cancer Agents Targeting Aldo‐Keto Reductase (AKR) 1C3 Protein by Pharmacophore Modeling, Virtual Screening and Molecular Docking(2021)2 cited
• → Drug discovery by integration of pharmacophore modeling, virtual screening and biological evaluation by means of bioinformatics resources(2016)