The bioisosteric similarity of the tetrazole and carboxylate anions: Clues from the topologies of the electrostatic potential and of the electron density

Chérif F. Matta, Alya A. Arabi, Donald F. Weaver

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

There is a need for an a priori method with which to demonstrate the physical similarities between non-classical bioisosteres. In this study we explore the utility of the electron density and the electrostatic potential as the basis for a systematic investigation of the physical and chemical similarities between bioisosteres. The tetrazole and carboxylate bioisosteric pair is used as an illustrative example. It is shown that tetrazole and carboxylate anions give rise to electrostatic potentials (ESP) that exhibit a remarkable local similarity in the disposition of four coplanar local minima at positions consistent with lone pairs. The similarity of the disposition of these ESP minima generated by the two bioisosteres is in sharp contrast with their differences in the number and types of atoms, their nuclear geometrical arrangements, their total volumes, their partial charges, and their electron populations. The topology and geometrical disposition of these minima are shown to be independent of the capping group used in the model, and thus an inherent property of this bioisosteric pair. A model of the receptor region responsible for binding to either of these bioisosteres is proposed on the basis of an electrostatic "lock-and-key".

Original languageEnglish
Pages (from-to)1868-1872
Number of pages5
JournalEuropean Journal of Medicinal Chemistry
Volume45
Issue number5
DOIs
Publication statusPublished - May 2010
Externally publishedYes

Keywords

  • 5-Methyl tetrazole
  • Atomic properties
  • Bioisosterism
  • Drug design
  • Ethanoic acid
  • Molecular electrostatic potential
  • QTAIM

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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