ABSTRACT
The search for new antibacterial agents that could decrease bacterial resistance is a subject in continuous development. Gram-negative and Gram-positive bacteria possess a group of metalloproteins belonging to the MEROPS peptidase (M4) family, which is the main virulence factor of these bacteria. In this work, we used the previous results of a computational biochemistry protocol of a series of ligands designed in silico using thermolysin as a model for the search of antihypertensive agents. Here, thermolysin from Bacillus thermoproteolyticus, a metalloprotein of the M4 family, was used to determine the most promising candidate as an antibacterial agent. Our results from docking, molecular dynamics simulation, molecular mechanics Poisson-Boltzmann (MM-PBSA) method, ligand efficiency, and ADME-Tox properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity) indicate that the designed ligands were adequately oriented in the thermolysin active site. The Lig783, Lig2177, and Lig3444 compounds showed the best dynamic behavior; however, from the ADME-Tox calculated properties, Lig783 was selected as the unique antibacterial agent candidate amongst the designed ligands.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacillus/drug effects , Density Functional Theory , Enzyme Inhibitors/pharmacology , Thermolysin/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacillus/enzymology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Ligands , Models, Molecular , Molecular Structure , Thermolysin/metabolismABSTRACT
OBJECTIVE: To evaluate the effects of glucose-insulin-potassium (GIK) therapy on infarct size and left ventricular function when used as an adjuvant therapy to primary angioplasty. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Cardiac intensive care unit at a university hospital. PATIENTS: Thirty-seven patients with acute myocardial infarction for whom primary angioplasty was indicated. INTERVENTIONS: Eligible patients were randomized by a blinded pharmacist to GIK solution (30% glucose in water with insulin 50 U/L, and KCl 40 mM/L) vs. placebo at 1.5 mL/kg/hr for 24 hrs. MEASUREMENTS AND MAIN RESULTS: Tc 99m sestamibi myocardial scintigraphy was performed at admission and at 3 months. Primary end points were the changes in left ventricular ejection fraction (LVEF) and the size of salvaged myocardium. Baseline clinical characteristics were similar in both groups. At the 3-month follow-up, a significant overall decrease in infarct size (37 +/- 16% vs. 12 +/- 10%, p <.005) and an increase in LVEF (34 +/- 13% vs. 49 +/- 9%, p =.005) were observed. Patients randomized to GIK solution experienced a significant increase in their LVEF at 3 months (39 +/- 12 to 51 +/- 13, p =.002). Patients who received placebo had no significant differences between baseline and 3-month measurements (44 +/- 13 vs. 49 +/- 14, p = NS). There was a trend toward an increase in myocardial salvage in the GIK group, which did not reach statistical significance. When patients from both groups were compared directly, differences in LVEF improvement were no longer significant. CONCLUSIONS: GIK solution did not improve LVEF or decrease the infarct size among patients undergoing primary angioplasty.