Qualitative Estimation of Protein-Ligand Complex Stability through Thermal Titration Molecular Dynamics Simulations.
J Chem Inf Model
; 62(22): 5715-5728, 2022 Nov 28.
Article
in English
| MEDLINE | ID: covidwho-2096619
ABSTRACT
The prediction of ligand efficacy has long been linked to thermodynamic properties such as the equilibrium dissociation constant, which considers both the association and the dissociation rates of a defined protein-ligand complex. In the last 15 years, there has been a paradigm shift, with an increased interest in the determination of kinetic properties such as the drug-target residence time since they better correlate with ligand efficacy compared to other parameters. In this article, we present thermal titration molecular dynamics (TTMD), an alternative computational method that combines a series of molecular dynamics simulations performed at progressively increasing temperatures with a scoring function based on protein-ligand interaction fingerprints for the qualitative estimation of protein-ligand-binding stability. The protocol has been applied to four different pharmaceutically relevant test cases, including protein kinase CK1δ, protein kinase CK2, pyruvate dehydrogenase kinase 2, and SARS-CoV-2 main protease, on a variety of ligands with different sizes, structures, and experimentally determined affinity values. In all four cases, TTMD was successfully able to distinguish between high-affinity compounds (low nanomolar range) and low-affinity ones (micromolar), proving to be a useful screening tool for the prioritization of compounds in a drug discovery campaign.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Molecular Dynamics Simulation
/
COVID-19
Type of study:
Prognostic study
/
Qualitative research
Limits:
Humans
Language:
English
Journal:
J Chem Inf Model
Journal subject:
Medical Informatics
/
Chemistry
Year:
2022
Document Type:
Article
Affiliation country:
Acs.jcim.2c00995
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