http://192.168.1.40:8080/xmlui/handle/123456789/1477 Sun, 31 May 2026 15:24:09 GMT 2026-05-31T15:24:09Z http://192.168.1.40:8080/xmlui/handle/123456789/1506 Role of Protein Flexibility in the Discovery of New Drugs Fuentes, Gloria; Dastidar, Shubhra Ghosh; Madhumalar, Arumugam; Verma, Chandra S. Proteins have inherent flexibility, and this plays a critical role in a vast array of biological functions, including ligand binding. Structure-based drug design (SBDD) strategies incorporate biomolecular structures with computational methods to predict and optimize ligand–receptor complexes. However, these strategies largely involve using static protein snapshots derived by classical X-ray crystallography, and thus critical and valuable information on flexibility is completely absent. With a historical perspective, we highlight relevant fundamental aspects of the character and importance of the tapestry of flexibility in molecular recognition events, especially when a ligand binds to a protein. Knowledge of methods that can provide details of the full spectrum of flexibility in proteins is a requisite to laying the foundations for linking these concepts with the current algorithms employed in SBDD. Finally, we underline a number of examples that should urge the incorporation of protein flexibility in the industrial drug design pipeline. DOI: 10.1002/ddr.20399 Tue, 01 Feb 2011 00:00:00 GMT http://192.168.1.40:8080/xmlui/handle/123456789/1506 2011-02-01T00:00:00Z http://192.168.1.40:8080/xmlui/handle/123456789/1505 Moleculardynamicssimulations of Aβfibrilinteractions with β-sheetbreakerpeptides Bruce, Neil J.; Chen, Deliang; Dastidar, Shubhra Ghosh; Marks, Gabriel E.; Schein, Catherine H.; Bryce, Richard A. Accumulation and aggregation of the 42-residue amyloid-β (Aβ) protein fragment, which originates from the cleavage of amyloid precursor protein by β and γ secretase, correlates with the pathology of Alzheimer's disease (AD). Possible therapies for AD include peptides based on the Aβ sequence, and recently identified small molecular weight compounds designed to mimic these, that interfere with the aggregation of Aβ and prevent its toxic effects on neuronal cells in culture. Here, we use moleculardynamicssimulations to compare the mode of interaction of an active (LPFFD) and inactive (LHFFD) β-sheetbreakerpeptide with an Aβfibril structure from solid-state NMR studies. We found that LHFFD had a weaker interaction with the fibril than the active peptide, LPFFD, from geometric and energetic considerations, as estimated by the MM/PBSA approach. Cluster analysis and computational alanine scanning identified important ligand–fibril contacts, including a possible difference in the effect of histidine on ligand–fibril π-stacking interactions, and the role of the proline residue in establishing contacts that compete with those essential for maintenance of the inter-monomer β-sheet structure of the fibril. Our results show that moleculardynamicssimulations can be a useful way to classify the stability of docking sites. These mechanistic insights into the ability of LPFFD to reverse aggregation of toxic Aβ will guide the redesign of lead compounds, and aid in developing realistic therapies for AD and other diseases of protein aggregation. DOI: 10.1016/j.peptides.2010.07.015 Mon, 01 Nov 2010 00:00:00 GMT http://192.168.1.40:8080/xmlui/handle/123456789/1505 2010-11-01T00:00:00Z