Work

Identification of BRAF Inhibitors through In Silico Screening

Year: 2008

Type: article

Abstract: The BRAF protein kinase, a molecule in the RAS-RAF-MEK-ERK signaling pathway, is mutated to harbor elevated kinase activity in approximately 7% of human cancers, which makes it an important therapeutic target for inhibition. Several BRAF protein-kinase inhibitors have been developed through high-throughout screening in vitro; however, many of these compounds suffer from a lack of suitable kinase specificity and other chemotherapeutic properties. In silico screening has evolved as a powerful complimentary approach to protein-kinase inhibitor identification. Here we describe an in silico screen for BRAF inhibitors that leads to the identification of a series of purine-2,6-dione analogues with IC50 values in the single-digit micromolar range and with significant selectivity for BRAF over other representative protein kinases. The binding modes of these inhibitors to BRAF are analyzed through molecular docking to derive structure-activity relationships and to assist in the future development of more potent and more specific BRAF inhibitors.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/jm800539g

Authors: Cheng Luo, Peng Xie, Ronen Marmorstein

Institutions: The Wistar Institute, University of Pennsylvania

Language: English

Topic: Computational Drug Discovery Methods

Subfield: Computational Theory and Mathematics

Field: Computer Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Cancer Institute