Molecular dynamic simulations of the catalytic subunit of calpains 1, 2, 5, and 10: Structural analysis with an aim toward drug design

Our atomistic simulations confirmed the importance of calcium ions for the structure of calpains and their functionality. With these models and their subsequent use in molecular docking, essential structural requirements were identified for the binding of ligands to the calpain catalytic site that provide useful information for the design of new selective calpain inhibitors. The results from this work are currently being completed with both calculations and experiments searching for new now ‐classical calpain selective inhibitors. Calpains are cysteine proteases involved in the development of several human chronic illnesses such as neurodegenerative diseases, cardiovascular ailments, diabetes, and obesity which constitutes them into possible therapeutic targets. Here, using molecular dynamic simulations and docking, we studied the binding of known inhibitors to representative members of classical and nonclassical calpains. Our aim is to gain better understanding on the inhibition mechanism of calpains and to develop better and more specific inhibitors. Our atomistic models confirmed the importance of calcium ions for the structure of calpains and, as a consequence, their functionality. With these models and their subsequent use in molecular docking, essential structural requirements were identified for the binding of ligands to the calpain catalytic site that provide useful information for the design of new selective calpain inhibitors.

Source: Chemical Biology and Drug Design - November 25, 2018 Category: Biology Authors: Antonio Romo ‐Mancillas, Roselyn Lemus, Raúl Pérez‐Estrada, Francisco Kuribreña‐Romero de Terreros, Lenin Domínguez‐Ramírez Tags: RESEARCH ARTICLE Source Type: research