Active site acidic residues and structural analysis of modelled human aromatase: A potential drug target for breast cancer

Abstract

This study sheds new light on the role of acidic residues present in the active site cavity of human aromatase. Eight acidic residues (E129, D222, E245, E302, D309, E379, D380 and D476) lining the cavity are identified and studied using comparative modeling, docking, molecular dynamics as well as statistical techniques. The structural environment of these acidic residues is studied to assess the stability of the corresponding carboxylate anions. Results indicate that the environment of the residues E245, E302 and D222 is most suitable for carboxylate ion formation in the uncomplexed form. However, the stability of D309, D222 and D476 anions is seen to increase on complexation to steroidal substrates. In particular, the interaction between D309 and T310, which assists proton transfer, is found to be formed following androgen/nor-androgen complexation. The residue D309 is found to be clamped in the presence of substrate which is not observed in the case of the other residues although they exhibit changes in properties following substrate binding. Information entropic analysis indicates that the residues D309, D222 and D476 have more conformational flexibility compared to E302 and E245 prior to substrate binding. Interaction similar to that between D476 and D309, which is expected to assist androgen aromatization, is proposed between E302 and E245. The inhibition of aromatase activity by 4-hydroxy androstenedione (formestane) is attributed to a critical hydrogen bond formation between the hydroxy moiety and T310/D309 as well as the large distance from D476. The results corroborate well with earlier site directed mutagenesis studies.

Synthesis, evaluation of 6,8-dibromo-2-aryl-2,3-dihydroquinolin-4(1H)-ones in MCF-7 (breast cancer) cell lines and their docking studies

“…With an objective of designing new and potent AIs (Murthy et al, 2006;Rao and Murthy, 2009), we relied on flavonoid nucleus as a structural scaffold and by bioisosteric modification on ring oxygen with nitrogen led to a series of 6,8-dibromo-2-aryl-2,3-dihydroquinolin-4(1H)-one derivatives. We took clue from the most active bromo derivative YM511 (Okada et al, 1996) and introduced bromo group in our compounds.…”

Design and pharmacophoric identification of flavonoid scaffold‐based aromatase inhibitors

“…The docking scoring functions are made deliberate using docking protocols including strength of protein and the docked ligand complex. [49] All these docking score are essential for the selection of the best conformation of each compound. The top docked conformations with the highest negative energy has been considered as the optimum pose, and taken to distinguish the considerable interaction between amino acid residues of human placental aromatase and the optimum conformations of each ligand.…”

Synthesis of antihyperglycemic, α-glucosidase inhibitory, and DPPH free radical scavenging furanochalcones

“…We report herein synthesis of new furanochalcones and their ability of inhibiting rat intestinal a-glucosidase and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activities. Our earlier studies employing homology modeling, (Murthy et al, 2005;Chourasia et al, 2005;Reddy et al, 2006) docking (Ravindra et al, 2008), QSAR (Srivani and Sastry, 2009) were helpful in examining the interactions of the synthesized inhibitors with a-glucosidase and develop structure-activity relationship. We also report antihyperglycemic activity of most potent a-glucosidase inhibitor in starch-induced PPHG in rats.…”