This proposal represents a request for continued support of our ongoing project exploring receptor-ligand interactions and the thermodynamics of ligand binding to biological receptors. The overall objectives are aimed at developing and applying novel methods of free energy simulations to ligand binding thermodynamics, docking and receptor-ligand interaction modeling. Specific efforts are directed to the development of a hierarchy of methods that provide suitable tools for high-throughput screening, as well as detailed ligand refinement techniques employing accurate atomic force fields and adequate thermodynamic sampling. The primary goals of the current proposal are (i) the continued development, implementation and assessment of flexible receptor ? flexible ligand docking approaches, augmenting the previously developed CDOCKER pipeline with flexible receptor sampling, improved sampling approaches and new approaches to consider the increasingly important approach tethered-ligand inhibitor design, and (ii) the development of free energy based simulation methods to enable multi-site lambda dynamics free energy calculations that provide a scalable means of exploring large chemical landscapes of substituent and protein side chains in the optimization of inhibitors that are responsive to resistant mutations in receptor pockets. The former method development is driven by collaborative studies to identify and develop mimics of transcriptional activation domains (TADs) based on amphipathic small molecules, initially targeting activation through interactions with KIX domains of the CREB binding protein and the AciD domain of Med25. Driving biomedical questions concerning the development of small molecule inhibitors for key cancer targets such as menin-MLL protein-protein interaction inhibition and the development and exploration of inhibitors of acyl protein thioesterases, targeted in anti- cancer therapies for oncogenic HRas, will be addressed through collaborative studies that aim to establish robust in silico screening approaches of small molecules against their receptor targets and resistance mutants.
High throughput computer based docking and free energy simulation methods will be developed and applied to address the discovery, design and refinement of small molecule inhibitors for control of transcriptional activation, for the inhibition of acyl protein thioesterases and of protein-protein interactions targeting in HRas anti-oncogenics associated with menin-MLL interaction disruption.
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