Optimization of CHARMM force field parameters for ryanodine receptor inhibitory drug dantrolene using FFTK and FFParam.

Sefer Baday, Cemil Can Saylan, Saliha Nur Uludag, Adem Tekin

Journal: Journal of molecular modeling 2024;30(2):46

PMID: 38261112

Abstract

CONTEXT

Ryanodine receptors (RyRs) are large intracellular ligand-gated calcium release ion channels. Mutations in human RyR1 in combination with a volatile anesthetic or muscle relaxant are known to cause leaky RyRs resulting in malignant hyperthermia (MH). This has long been primarily treated with the RyR inhibitory drug dantrolene. Alternatives to dantrolene as a RyR inhibitor may be found through computer-aided drug design. Additionally, molecular dynamics (MD) studies of dantrolene interacting with RyRs may reveal its full mechanism of action. The availability of accurate force field parameters is important for the success of both.

METHODS

In this study, force field parameters for dantrolene were obtained from the CHARMM General Force Field (CGenFF) program and optimized using the force field toolkit (FFTK) and FFParam programs. The obtained parameters were then validated by a comparison between calculated and experimental IR spectra and normal mode analysis, among other techniques.

Address: Computational Science and Engineering Department, Informatics Institute, Istanbul Technical University, Ayazaga Campus, Maslak, 34469, Istanbul, Türkiye.; Computational Science and Engineering Department, Informatics Institute, Istanbul Technical University, Ayazaga Campus, Maslak, 34469, Istanbul, Türkiye.; Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich (TUM), Munich, Germany.; Computational Science and Engineering Department, Informatics Institute, Istanbul Technical University, Ayazaga Campus, Maslak, 34469, Istanbul, Türkiye.; TÜBİTAK Research Institute for Fundamental Sciences, 41470, Gebze, Kocaeli, Türkiye.; Computational Science and Engineering Department, Informatics Institute, Istanbul Technical University, Ayazaga Campus, Maslak, 34469, Istanbul, Türkiye. [email protected].; Applied Informatics Department, Informatics Institute, Istanbul Technical University, 34469, Istanbul, Türkiye. [email protected].; Artificial Intelligence and Data Engineering Department, Faculty of Computer Informatics and Engineering, Istanbul Technical University, 34469, Istanbul, Türkiye. [email protected].

DOI: 10.1007/s00894-024-05841-3

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https://dx.doi.org/10.1007/s00894-024-05841-3

MeSH Terms: Humans, Dantrolene, Ryanodine Receptor Calcium Release Channel, Calcium, Drug Design, Mutation