Design of selective TACE inhibitors using molecular docking studies: Synthesis and preliminary evaluation of anti-inflammatory and TACE inhibitory activity.

Tumor necrosis factor-α (TNF-α) converting enzyme (TACE) has been considered one of the principal therapeutic targets for the treatment of TNF-dependent pathologies. Several TACE inhibitors have been reported, but none of them has been successfully passed to phase II clinical trials. In the present work, we attempted to design highly selective new non-hydroxamate sulfonamide TACE inhibitors. The docking study was performed on one of the crystal structures of TACE, selected based on its resolution and R value, to tackle the flexibility issue of the active site. The results allowed us to distinguish the analogues with a higher binding affinity toward the active site of TACE and to identify the substituent of analogues needed for binding with the surrounding site of the enzyme. Finally the analogues were docked on crystal structures of six different matrix metalloproteinases (MMPs) for a selectivity study of TACE over MMPs. Some of these analogues were synthesized and subjected to preliminary testing for in vivo anti-inflammatory activity and TACE inhibitory activity.

Estimation of the Long-term Cardiovascular Events Using UKPDS Risk Engine in Metabolic Syndrome Patients.

Long-term cardiovascular complications in metabolic syndrome are a major cause of mortality and morbidity in India and forecasted estimates in this domain of research are scarcely reported in the literature. The aim of present investigation is to estimate the cardiovascular events associated with a representative Indian population of patients suffering from metabolic syndrome using United Kingdom Prospective Diabetes Study risk engine. Patient level data was collated from 567 patients suffering from metabolic syndrome through structured interviews and physician records regarding the input variables, which were entered into the United Kingdom Prospective Diabetes Study risk engine. The patients of metabolic syndrome were selected according to guidelines of National Cholesterol Education Program - Adult Treatment Panel III, modified National Cholesterol Education Program - Adult Treatment Panel III and International Diabetes Federation criteria. A projection for 10 simulated years was run on the engine and output was determined. The data for each patient was processed using the United Kingdom Prospective Diabetes Study risk engine to calculate an estimate of the forecasted value for the cardiovascular complications after a period of 10 years. The absolute risk (95% confidence interval) for coronary heart disease, fatal coronary heart disease, stroke and fatal stroke for 10 years was 3.79 (1.5-3.2), 9.6 (6.8-10.7), 7.91 (6.5-9.9) and 3.57 (2.3-4.5), respectively. The relative risk (95% confidence interval) for coronary heart disease, fatal coronary heart disease, stroke and fatal stroke was 17.8 (12.98-19.99), 7 (6.7-7.2), 5.9 (4.0-6.6) and 4.7 (3.2-5.7), respectively. Simulated projections of metabolic syndrome patients predict serious life-threatening cardiovascular consequences in the representative cohort of patients in western India.