Insights into the structure and inhibition of <i>Giardia intestinalis</i> arginine deiminase: homology modeling, docking, and molecular dynamics studies

<p><i>Giardia intestinalis</i> arginine deiminase (<i>GiADI</i>) is an important metabolic enzyme involved in the energy production and defense of this protozoan parasite. The lack of this enzyme in the human host makes <i>GiADI</i> an attractive target for drug design against <i>G. intestinalis</i>. One approach in the design of inhibitors of <i>GiADI</i> could be computer-assisted studies of its crystal structure, such as docking; however, the required crystallographic structure of the enzyme still remains unresolved. Because of its relevance, in this work, we present a three-dimensional structure of <i>GiADI</i> obtained from its amino acid sequence using the homology modeling approximation. Furthermore, we present an approximation of the most stable dimeric structure of <i>GiADI</i> identified through molecular dynamics simulation studies. An <i>in silico</i> analysis of druggability using the structure of <i>GiADI</i> was carried out in order to know if it is a good target for design and optimization of selective inhibitors. Potential <i>GiADI</i> inhibitors were identified by docking of a set of 3196 commercial and 19 <i>in</i>-<i>house</i> benzimidazole derivatives, and molecular dynamics simulation studies were used to evaluate the stability of the ligand–enzyme complexes.</p

Chemical Analysis and Antidiabetic Potential of a Decoction from <i>Stevia serrata</i> Roots

A decoction of the roots (31.6–316 mg/kg) from Stevia serrata Cav. (Asteraceae) as well as the main component (5–150 mg/kg) showed hypoglycemic and antihyperglycemic effects in mice. The fractionation of the active extract led to the isolation of dammaradiene acetate (1), stevisalioside A (2), and three new chemical entities characterized by spectroscopic methods and named stevisaliosides B–D (3–5). Glycoside 2 (5 and 50 mg/kg) decreased blood glucose levels and the postprandial peak during oral glucose and insulin tolerance tests in STZ-hyperglycemic mice. Compounds 1–5 were tested also against PTP1B1–400 and showed IC50 values of 1180.9 ± 0.33, 526.8 ± 0.02, 532.1 ± 0.03, 928.2 ± 0.39, and 31.8 ± 1.09 μM, respectively. Compound 5 showed an IC50 value comparable to that of ursolic acid (IC50 = 30.7 ± 0.00 μM). Docking studies revealed that 2–5 and their aglycones bind to PTP1B1–400 in a pocket formed by the C-terminal region. The volatilome of S. serrata was characterized by a high content of (E)-longipinene, spathulenol, guaiadiene, seychellene, and aromandendrene. Finally, a UHPLC-UV method was developed and validated to quantify the content of 2 in the decoction of the plant

Chemical Analysis and Antidiabetic Potential of a Decoction from <i>Stevia serrata</i> Roots

A decoction of the roots (31.6–316 mg/kg) from Stevia serrata Cav. (Asteraceae) as well as the main component (5–150 mg/kg) showed hypoglycemic and antihyperglycemic effects in mice. The fractionation of the active extract led to the isolation of dammaradiene acetate (1), stevisalioside A (2), and three new chemical entities characterized by spectroscopic methods and named stevisaliosides B–D (3–5). Glycoside 2 (5 and 50 mg/kg) decreased blood glucose levels and the postprandial peak during oral glucose and insulin tolerance tests in STZ-hyperglycemic mice. Compounds 1–5 were tested also against PTP1B1–400 and showed IC50 values of 1180.9 ± 0.33, 526.8 ± 0.02, 532.1 ± 0.03, 928.2 ± 0.39, and 31.8 ± 1.09 μM, respectively. Compound 5 showed an IC50 value comparable to that of ursolic acid (IC50 = 30.7 ± 0.00 μM). Docking studies revealed that 2–5 and their aglycones bind to PTP1B1–400 in a pocket formed by the C-terminal region. The volatilome of S. serrata was characterized by a high content of (E)-longipinene, spathulenol, guaiadiene, seychellene, and aromandendrene. Finally, a UHPLC-UV method was developed and validated to quantify the content of 2 in the decoction of the plant