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Structural dynamics and allostery of Rab proteins: strategies for drug discovery and design

Rab proteins represent the largest family of the Rab superfamily guanosine triphosphatase (GTPase). Aberrant human Rab proteins are associated with multiple diseases, including cancers and neurological disorders. Rab subfamily members display subtle conformational variations that render specificity in their physiological functions and can be targeted for subfamily-specific drug design. However, drug discovery efforts have not focused much on targeting Rab allosteric non-nucleotide binding sites which are subjected to less evolutionary pressures to be conserved, hence are likely to offer subfamily specificity and may be less prone to undesirable off-target interactions and side effects. To discover druggable allosteric binding sites, Rab structural dynamics need to be first incorporated using multiple experimentally and computationally obtained structures. The high-dimensional structural data may necessitate feature extraction methods to identify manageable representative structures for subsequent analyses. We have detailed state-of-the-art computational methods to (i) identify binding sites using data on sequence, shape, energy, etc., (ii) determine the allosteric nature of these binding sites based on structural ensembles, residue networks and correlated motions and (iii) identify small molecule binders through structure- and ligand-based virtual screening. To benefit future studies for targeting Rab allosteric sites, we herein detail a refined workflow comprising multiple available computational methods, which have been successfully used alone or in combinations. This workflow is also applicable for drug discovery efforts targeting other medically important proteins. Depending on the structural dynamics of proteins of interest, researchers can select suitable strategies for allosteric drug discovery and design, from the resources of computational methods and tools enlisted in the workflow.