Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

Abstract

Abstract:The angiotensin II (Ang II) type 1 and type 2 receptors (AT1R and AT2R) orchestrate an array of biological processes that regulate human health. Aberrant function of these receptors triggers pathophysiological responses that can ultimately lead to death. Therefore, it is important to design and synthesize compounds that affect beneficially these two receptors. Cardiovascular disease, which is attributed to the overactivation of the vasoactive peptide hormone Αng II, can now be treated with commercial AT1R antagonists. Herein, recent achievements in rational drug design and synthesis of molecules acting on the two AT receptors are reviewed. Quantitative structure activity relationships (QSAR) and molecular modeling on the two receptors aim to assist the search for new active compounds. As AT1R and AT2R are GPCRs and drug action is localized in the transmembrane region the role of membrane bilayers is exploited. The future perspectives in this field are outlined. Tremendous progress in the field is expected if the two receptors are crystallized, as this will assist the structure based screening of the chemical space and lead to new potent therapeutic agents in cardiovascular and other diseases.

FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC): study protocol for randomized controlled trial

“…Fimasartan has theoretically similar lipophilicity and half-life to those of losartan [25]. However, fimasartan has higher potency and stronger efficacy than does losartan [26].…”

Effect of dietary fibers on losartan uptake and transport in Caco‐2 cells

“…The membrane fluidity is low in the cholesterol rich liposome . Biological membranes play an essential role in constituting the first interaction site for drugs to exert their biological action, and studies of losartan–membrane interactions have been performed using model membranes . Hodzic et al .…”

“…The membrane fluidity is low in the cholesterol rich liposome [27]. Biological membranes play an essential role in constituting the first interaction site for drugs to exert their biological action, and studies of losartan-membrane interactions have been performed using model membranes [23,[28][29][30]. Hodzic et al [23] suggested that partitioning of losartan into the membrane confers a negative charge to the lipid bilayers and that losartan is likely to be excluded from the cholesterol-rich rafts.…”

Recent contributions of structure-based drug design to the development of antibacterial compounds

“…In addition to traditional SBDD there are numerous other methods and variations that utilize protein structure in the discovery and development of new drug entities, including X-ray crystallography- and NMR-based fragment screening, and virtual ( in silico ) screening [1, 2]. Several previous reviews have discussed the techniques and technology of SBDD, as well as the application of SBDD methods towards the development of new drug molecules [3, 4]. Here we will summarize recent applications of structure-based methods for the development of antibacterial agents.…”