An integrated QSAR modeling approach to explore the structure-property and selectivity relationships of N-benzoyl-L-biphenylalanines as integrin antagonists

Mol Divers. 2018 Feb;22(1):129-158. doi: 10.1007/s11030-017-9789-9. Epub 2017 Nov 17.

Abstract

Integrins [Formula: see text] and [Formula: see text] are important targets to treat different inflammatory diseases, such as multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, atherosclerosis, and asthma. Despite being valuable targets, only a few work has been reported to date regarding molecular modeling studies on these integrins. Not only that, none of these reports addressed the selectivity issue between integrins [Formula: see text] and [Formula: see text]. Therefore, a major challenge regarding the design and discovery of selective integrin antagonists remains. In this study, a series of 142 N-benzoyl-L-biphenylalanines having both integrin [Formula: see text] and [Formula: see text] inhibitory activities were considered for a variety of QSAR approaches including regression and classification-based 2D-QSARs, Hologram QSARs, 3D-QSAR CoMFA and CoMSIA studies to identify the structural requirements of these integrin antagonists. All these QSAR models were statistically validated and subsequently correlated with each other to get a detailed understanding of the activity and selectivity profiles of these molecules.

Keywords: 3D-QSAR; Integrin; N-benzoyl-L-biphenylalanine; QAAR; QSAAR; Selectivity.

MeSH terms

  • Algorithms
  • Bayes Theorem
  • Computer Simulation
  • Drug Design
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Integrins / antagonists & inhibitors
  • Integrins / chemistry*
  • Ligands
  • Models, Molecular*
  • Molecular Structure
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / chemical synthesis*
  • Phenylalanine / pharmacology*
  • Protein Binding
  • Protein Multimerization / drug effects
  • Quantitative Structure-Activity Relationship*

Substances

  • Integrins
  • Ligands
  • Phenylalanine