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Dynamic Molecular Mechanisms and Drug Design of Important Therapeutic Targets
Pawnikar, Shristi
Pawnikar, Shristi
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Abstract
Membrane proteins, such as G protein-coupled receptors (GPCRs), and soluble proteins play critical roles in a wide range of physiological and pathological cellular processes. GPCRs constitute the largest family of drug targets. The CXCR4 chemokine receptor, in particular, helps promote HIV entry into host cells. Polycystin-1 (PC1) is an atypical GPCR with 11 transmembrane domains. Mutations in the PC1 protein are responsible for the majority cases of a potentially lethal human autosomal dominant polycystic kidney disease (ADPKD). Moreover, small ubiquitin-like modifiers (SUMO) play an important role in regulation of post-translational modifications. Alterations in the SUMO E1 enzymes is linked to life-threatening neurogenerative disorders, viral infections and cancers. Gaussian accelerated molecular dynamics (GaMD) has been successful in simulating complex biological processes including ligand binding, protein-protein/membrane/nucleic acid interactions, protein folding and GPCR activation. Additionally, Ligand GaMD (LiGaMD) and Peptide GaMD (Pep-GaMD) methods were further developed to model ligand and peptide binding/unbinding, respectively, through improved enhanced sampling. Here, molecular mechanisms of small molecule and peptide mediated activation of important therapeutic targets have been uncovered using powerful computational techniques (including GaMD, LiGaMD, Pep-GaMD, molecular docking and homology modeling) and collaborative experiments.
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2023-05-31
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University of Kansas
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990705_1.pdf
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Computational chemistry, drug design, enhanced sampling, GPCRs, molecular dynamics, peptide agonists, small-molecule