Method of exploring the flexibility of macromolecular targets and its use in rational drug design

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Modesto Orozco LopezOliver CarrilloRima Chaudhuri,  CHARLES ANTHONY LAUGHTON
Barcelona Supercomputing Center - Centro Nacional De Supercomputacion (BSC-CNS), Fundacio Institut De Recerca Biomedica (IRB), Universitat de Barcelona, University of Nottingham


It comprises a method of exploring the flexibility of macromolecules, where an available ensemble of structures of a receptor, such as one coming from a molecular dynamics trajectory or a set of experimentally derived structures, is used to generate an ensemble of structures for a closely related receptor, such as a receptor mutant, a receptor with a series of post-translational modifications, or one that is non-covalently bound to a second molecule. In this way, new ensembles of the pertubed receptor can be accessed without the need to explicitely simulate the new system. The method allows the study of structure and flexibility of derivatives and relatives of a receptor in a computer efficient manner, and therefore has applications in the rational-drug design field, especially in virtual screening. It also comprises a computer program product for causing a computer to perform the method, as well as a system of molecular modeling comprising computer means for carrying out each of the steps of the method.