Toward structure-based drug design against the epidermal growth factor receptor (EGFR). Issue 2 (February 2021)

• Record Type: Journal Article
• Authors: Haddad, Yazan; Remes, Marek; Adam, Vojtech; Heger, Zbynek
• Is Part Of: Drug discovery today. Volume 26:Issue 2(2021)
• Page Start: 289
• Page End: 295
• Publication Date: 2021-02
• Subjects: Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2020.10.007
• Languages: English
• ISSNs: 1359-6446

Abstract

Highlights: Structural variations in EGFR should not be ignored in structure-based drug design. Main variations involve inward and outward folding of C-helix in the kinase N-lobe. Origins of variations are mutations and drug R-groups but not the drug core. Comparative modeling, fitting and clustering are imperative steps in EGFR drug design. Alternatively, volume and shape of binding site can be used to filter ligands against structures. Abstract : Most of the available crystal structures of epidermal growth factor receptor (EGFR) kinase domain, bound to drug inhibitors, originated from ligand-based drug design studies. Here, we used variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. The families shared similar mutational profiles and similarity in the ligand R-groups (chemical composition, geometry, and charge) facing the C-helix, mutation sites, and DFG domain. For structure-based drug design, we recommend a systematic decision-making process for choice of template, guided by appropriate pairwise fitting and clustering before the molecular docking step. Alternatively, the binding site shape/volume can be used to filter and select the compound libraries. Teaser: The article delineates structural features crucial for EGFR structure-based drug design and provides a rationale for the use of EGFR structure families for drug discovery applications.