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Indolyl-pyrrolone as a new scaffold for Pim1 inhibitors
Stefania Olla1, Fabrizio Manetti, Emmanuele Crespan
1Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
Abstract:
Pim1 belongs to a family of serine/threonine kinases, which is involved in the control of cell growth, differentiation, and apoptosis. Pim1 plays a pivotal role in cytokine signaling and is implicated in the development of a large number of tumors, representing a very attractive target for anticancer therapy. In this work, we applied a virtual screening protocol aimed at identifying small molecules able to inhibit Pim1 activity. The search of novel inhibitors was performed through a structure-based molecular modeling approach, taking advantage of the availability of the three-dimensional crystal structure of inhibitors bound to Pim1. Starting from the knowledge of protein-ligand complexes, the software LigandScout was used to generate pharmacophoric models, in turn used as queries to perform a virtual screening of databases, followed by docking experiments. As a result, a restricted set of candidates for biological testing was identified. Finally, among the six compounds selected as potential inhibitors of Pim1, two candidates endowed with a significant activity against Pim1 emerged. Interestingly, one of these compounds has a chemical scaffold different from inhibitors previously identified.
Insights
Researchers identified novel small molecules that inhibit Pim1 kinase activity, a key factor in tumor development. Two potent inhibitors were discovered, including one with a unique chemical structure, offering new avenues for anticancer drug development.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Pim1 is a serine/threonine kinase crucial for cell growth, differentiation, and apoptosis.
- Pim1 is implicated in numerous cancers, making it a significant therapeutic target.
- Cytokine signaling pathways are regulated by Pim1 activity.
Purpose of the Study:
- To identify novel small molecules that inhibit Pim1 kinase activity using computational methods.
- To discover potential anticancer agents targeting Pim1.
- To explore new chemical scaffolds for Pim1 inhibition.
Main Methods:
- Structure-based virtual screening utilizing the 3D crystal structure of Pim1-inhibitor complexes.
- Generation of pharmacophoric models using LigandScout software.
- Docking experiments to evaluate potential inhibitor binding.
Main Results:
- A focused set of candidate molecules for biological evaluation was identified.
- Two compounds demonstrated significant inhibitory activity against Pim1.
- One identified inhibitor possesses a novel chemical scaffold distinct from previously known agents.
Conclusions:
- Virtual screening effectively identified potent Pim1 inhibitors.
- The discovery of a novel chemical scaffold offers new opportunities for drug design.
- These findings provide promising leads for developing new anticancer therapies targeting Pim1.
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