Structure-Function Study of Quinazolinone-Based Vitronectin Receptor (αVβ3) Antagonists: Computer-Assisted Analysis of Ligand-Receptor Interactions

Edward   C.   Lawson; William   A.   Kinney; Michael   J.   Costanzo; William   J.   Hoekstra; Jack   A.   Kauffman; Diane   K.   Luci; Rosemary      Santulli; Brett   A.   Tounge; Stephen   C.   Yabut; Patricia      Andrade-Gordon

Abstract

Modification of the pendant functionalities on a quinazolinone scaffold led to potent antagonist activity for integrin αVβ3 with selectivity over integrin αIIbβ3. Various guanidine mimetics, linkers, and arylsulfonamides were investigated to optimize the series. A molecular model was constructed based on a published X-ray structure and used to analyze ligand-receptor interactions. We identified key interactions for the quinazolinone and arylsulfonamide groups that may explain the changes in potency in the structure-function study.

Keywords: Quinazolinone, Vitronectin Receptor, Ligand-Receptor

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Letters in Drug Design & Discovery

Title: Structure-Function Study of Quinazolinone-Based Vitronectin Receptor (αVβ3) Antagonists: Computer-Assisted Analysis of Ligand-Receptor Interactions

Volume: 1 Issue: 1

Author(s): Edward C. Lawson, William A. Kinney, Michael J. Costanzo, William J. Hoekstra, Jack A. Kauffman, Diane K. Luci, Rosemary Santulli, Brett A. Tounge, Stephen C. Yabut and Patricia Andrade-Gordon

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Keywords: Quinazolinone, Vitronectin Receptor, Ligand-Receptor

Abstract: Modification of the pendant functionalities on a quinazolinone scaffold led to potent antagonist activity for integrin αVβ3 with selectivity over integrin αIIbβ3. Various guanidine mimetics, linkers, and arylsulfonamides were investigated to optimize the series. A molecular model was constructed based on a published X-ray structure and used to analyze ligand-receptor interactions. We identified key interactions for the quinazolinone and arylsulfonamide groups that may explain the changes in potency in the structure-function study.

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Lawson C. Edward, Kinney A. William, Costanzo J. Michael, Hoekstra J. William, Kauffman A. Jack, Luci K. Diane, Santulli Rosemary, Tounge A. Brett, Yabut C. Stephen and Andrade-Gordon Patricia, Structure-Function Study of Quinazolinone-Based Vitronectin Receptor (αVβ3) Antagonists: Computer-Assisted Analysis of Ligand-Receptor Interactions, Letters in Drug Design & Discovery 2004; 1 (1) . https://dx.doi.org/10.2174/1570180043485644