Biology subjects

Walker, J. K.

Publications and source records attributed to Walker, J. K..

5 recordsLinked to original sources

bioRxiv2024

Computational structural prediction and chemical inhibition of the human mitochondrial pyruvate carrier protein heterodimer complex

The mitochondrial pyruvate carrier (MPC) plays a role in numerous diseases including neurodegeneration, metabolically dependent cancers, and the development of insulin resistance. Several previous studies in genetic mouse models or with existing inhibitors suggest that inhibition of the MPC could be used as a viable therapeutic strategy in these diseases. However, the MPCs structure is unknown, making it difficult to screen for and develop therapeutically viable inhibitors. Currently known MPC inhibitors would make for poor drugs due to their poor pharmacokinetic properties, or in the case of the thiazolidinediones (TZDs), off-target specificity for peroxisome-proliferator activated receptor gamma (PPAR{gamma}) leads to unwanted side effects. In this study, we develop several structural models for the MPC heterodimer complex and investigate the chemical interactions required for the binding of these known inhibitors to MPC and PPAR{gamma}. Based on these models, the MPC most likely takes on outward-facing (OF) and inward-facing (IF) conformations during pyruvate transport, and inhibitors likely plug the carrier to inhibit pyruvate transport. Although some chemical interactions are similar between MPC and PPAR{gamma} binding, there is likely enough difference to reduce PPAR{gamma} specificity for future development of novel, more specific MPC inhibitors.

biochemistry↗

bioRxiv2023

Predicting Permeation of Compounds across the Outer Membrane of P. aeruginosa Using Molecular Descriptors: Advantages and Limitations

The ability of Gram-negative pathogens to adapt and protect themselves against antibiotics is a growing threat to public health. The low permeability of the outer membrane (OM) in combination with effective multidrug efflux pumps, constitute the two main antibiotic resistance mechanisms. Though much efforts have been devoted to discover new antibiotics that can bypass these defense mechanisms, no new antibiotic classes have been introduced into clinics in the last 35 years. Models that identify specific descriptors of molecular properties and predict the likelihood that a given compound is capable of successfully permeate the OM and inhibit bacterial growth while avoiding efflux could facilitate the discovery of novel classes of antibiotics. Here we evaluate 174 molecular descriptors of 1260 antimicrobial compounds and study their correlations with antibacterial activity in Gram-negative Pseudomonas aeruginosa. While part of these descriptors are computed using traditional approaches based on the physicochemical properties intrinsic to the compounds, ensemble docking and all-atom molecular dynamics (MD) simulations are used to derive additional bacterium-specific mechanistic properties. Descriptors of compound permeation across the OM were calculated using all-atom MD simulations of the compounds in different subregions of the OM model. Descriptors of interactions with efflux pumps were calculated from ensemble docking of compounds targeting specific binding pockets of MexB, the major efflux transporter of P. aeruginosa. Using these descriptors and the measured antibacterial inhibitory concentrations of compounds, we design and implement a statistical protocol to identify a subset of the molecular properties that are predictive of whether a given compound is a strong or weak permeator across the Gram-negative OM. Our results indicate that 88.4% of the compounds that show measurable antibacterial activity, follow very consistent rules of permeation, which highlight the critical role that the interaction between the compound and the OM have at predicting permeation. The remaining 11.6% of the compounds, although less predictive, are characterized by distinctive structural markers that can be used to minimize classification errors. An implementation of the permeation rules and the structural markers uncovered in our study is shown, and it demonstrates the accuracy of our approach in a set of previously unseen compounds. Taken together, our analysis sheds new light on the key molecular properties that drug candidates should have in order to be effective at OM permeation/inhibition of P. aeruginosa, and opens the gate to similar data-driven studies in other Gram-negative pathogens.

biophysics↗

bioRxiv2022

A Synthetic ERRα Agonist Induces an Acute AerobicExercise Response and Enhances Exercise Capacity

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Here we report the identification of a synthetic agonist for the orphan nuclear receptor ERR (estrogen receptor-related receptor ), SLU-PP-332, that activates an acute aerobic exercise genetic program in skeletal muscle in an ERR-dependent manner. SLU-PP-332 increases mitochondrial function and cellular respiration consistent with induction of this genetic program. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. These data indicate the feasibility of targeting ERR for development of compounds that act as exercise mimetics that may be effective in treatment of numerous metabolic disorders and to improve muscle function in the aging.

pharmacology and toxicology↗

bioRxiv2022

Novel ERR pan-agonists ameliorate heart failure through boosting cardiac fatty acid metabolism and mitochondrial function

Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERR and ERR{gamma} are essential regulators for cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for heart failure. However, no natural or synthetic ERR agonist is available to demonstrate their pharmacological effect in vivo. Using a structure-based design approach, we designed and synthesized two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915), which significantly improved ejection fraction and ameliorated fibrosis against pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad-spectrum of metabolic genes were transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function, which were mainly mediated by ERR{gamma}. Metabolomics analysis showed significant normalization of metabolic profiles in fatty acid/lipid and TCA/OXPHOS metabolites by 915 in the mouse heart with 6-week pressure overload. Autophagy was also induced by ERR agonists in cardiomycoyte. On the other hand, ERR agonism led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocyte. In summary, ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failure in vivo. Our results provided direct pharmacological evidence supporting the further development of ERR agonists as novel heart failure therapeutics in vivo.

pharmacology and toxicology↗

bioRxiv2021

A repurposed drug screen identifies compounds that inhibit the binding of the COVID-19 spike protein to ACE2

Repurposed drugs that block the interaction between the SARS-CoV-2 spike protein and its receptor ACE2 could offer a rapid route to novel COVID-19 treatments or prophylactics. Here, we screened 2701 compounds from a commercial library of drugs approved by international regulatory agencies for their ability to inhibit the binding of recombinant, trimeric SARS-CoV-2 spike protein to recombinant human ACE2. We identified 56 compounds that inhibited binding by <90%, measured the EC50 of binding inhibition, and computationally modeled the docking of the best inhibitors to both Spike and ACE2. These results highlight an effective screening approach to identify compounds capable of disrupting the Spike-ACE2 interaction as well as identifying several potential inhibitors that could serve as templates for future drug discovery efforts.

pharmacology and toxicology↗