3995603

Transition state ensemble and Unibinding kinetics driven inhibitor design of sEH protein

Date
March 19, 2024
Explore related products in the following collection:

For many drug targets, it has been shown that the kinetics of drug binding (e.g. on rate and off rate) is more predictive of drug efficacy than thermodynamic quantities alone. This motivates the development of predictive computational models that can be used to optimize compounds on the basis of their kinetics. The structural details underpinning these computational models are not only found in the bound state, but also in the short-lived ligand binding transition state: the highest free energy point along the (un)binding pathway. Although this transition state cannot be directly observed experimentally, due to its extremely short lifetime, recent successes have demonstrated that modeling of the ligand binding transition state is possible with the help of enhanced sampling methods for molecular dynamics. In our previous work we generated unbinding paths for an inhibitor of soluble epoxide hydrolase (sEH) with a residence time of 11 minutes. Here we computationally modeled unbinding events for five additional inhibitors of sEH with residence times ranging from 14.25 to 31.75 minutes, with our results recapitulating these experimental residence times to within an order of magnitude. The unbinding ensembles are analyzed in detail, focusing on features of the ligand binding transition state. We find that ligands with similar structures and similar bound poses can show significant differences in their ligand binding transition states, in terms of their spatial distribution and their interactions with specific protein residues. However we also find similarities across the transition state ensembles when examining more general features such as ligand degrees of freedom (dihedral angles). Together our work finds significant insights for rational, kinetics-based drug design.

Presenter

Speaker Image for Samik Bose
Postdoctoral Research Scholar, Michigan State University

Speakers

Speaker Image for Alex Dickson
Michigan State University

Related Products

Thumbnail for Develop new generation chemically-defined cell culture media: Reduce production cost of therapeutic proteins
Develop new generation chemically-defined cell culture media: Reduce production cost of therapeutic proteins
Cell culture media and process are the key influence factor in the manufacturing cost of biotherapeutics. OPM has developed a new generation chemically-defined CHO media that are proved to work with a variety of CHO clones, like CHO-DG44, CHO-K1, CHO ZN and CHO-S, etc…
Thumbnail for Developing a prophylactic antibody for malaria eradication in low- and middle-income countries (LMICs)
Developing a prophylactic antibody for malaria eradication in low- and middle-income countries (LMICs)
Malaria, a mosquito-transmitted parasitic disease, poses a significant mortality risk globally, especially in Low- and Middle-Income Countries (LMICs)…
Thumbnail for Intensified downstream connected processing of mAbs: PD to scale up for robust, cost effective, and agile manufacturing
Intensified downstream connected processing of mAbs: PD to scale up for robust, cost effective, and agile manufacturing
Connected processing is an intensification strategy where multiple operations are connected and processed in parallel enabling the manufacturer to achieve higher productivity, while keeping time and cost low…
Thumbnail for Membrane association of PIKfyve kinase domain in a weighted ensemble-Markov state model framework
Membrane association of PIKfyve kinase domain in a weighted ensemble-Markov state model framework
PIKfyve is the third member (type III) of the PIPK lipid kinase family which catalyzes the phosphorylation reaction of PI3P to generate PI(3,5)P2 molecules…