In-Silico Molecular Interaction and Pharmacokinetic Evaluation of Remimazolam and Major Intravenous Anesthetics Targeting GABAA Receptors

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DOI: 10.21522/TIJPH.2013.SE.24.05.Art011

Authors : Jaganathan Ramakrishnan, Manjupriya Jothi, Thamizhmathi Thangaraju

Abstract:

This study investigates the molecular interactions and pharmacokinetic properties of five intravenous anaesthetics Remimazolam, Midazolam, Propofol, Thiopental, and Etomidate with the γ-Aminobutyric acid type A (GABAA) receptor, a key mediator of inhibitory neurotransmission in the central nervous system. Using molecular docking analysis, we evaluated the binding affinities of these drugs to the GABAA neurotransmitter receptor. Remimazolam emerged as a promising candidate with a docking score of -6.9 kcal/mol, demonstrating strong and stable interactions with critical receptor residues such as THR96 and GLN65. Although Midazolam exhibited a slightly superior docking score of -7.1 kcal/mol, Remimazolam’s pharmacokinetic profile offers distinct advantages, including rapid onset, short duration of action, and a favourable safety profile with minimal risk of hepatotoxicity and skin sensitization. In comparison, Propofol, Thiopental, and Etomidate showed weaker binding affinities and raised safety concerns. These findings suggest that Remimazolam is a competitive and safer alternative to existing intravenous anaesthetics, particularly in outpatient settings and procedures requiring efficient anaesthetic management. This study contributes valuable insights into the clinical application of Remimazolam, reinforcing its potential as an effective choice in the realm of intravenous anaesthesia.

References:

[1].  Weir, C. J., Mitchell, S. J., Lambert, J. J., 2017, Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics. Br J Anaesth. 119: i167–i175. Doi:10.1093/bja/aex369.

[2].  Ramasamy, K., Shanmugasundaram, J., Manoharan, R., Subramanian, V., Kathirvelu, P., Vijayaraghavan, R., 2022, Anti-neuropathic effect of 7,3′-dihydroxyflavone in paclitaxel induced peripheral neuropathy in mice involving GABAA, KATP channel and adenosine receptors. Neurochem Int. 159: 105388. Doi: 10.1016/j.neuint.2022.105388.

[3].  Marimuthu M., 2021, Dental impactions performed under general anaesthesia - A retrospective study on the frequency and implications, Int J Dent Oral Sci. 1793–1796. Doi:10.19070/2377-8075-21000355.

[4].  Keerthika S, Mani G., 2021, Knowledge, attitude and practice of dentists towards dental procedures under general Anesthesia in children. J Pharm Res Int. 83–93. Doi:10.9734/jpri/2021/v33i20B31361.

[5].  Manivasagam D, Muthukrishnan A, Chaudary M., 2020, Assessment of effectiveness of local anesthesia with and without adrenaline in patients with cardiac disorders. Int J Pharm Res. 13. Doi:10.31838/ijpr/2021.13.01.217.

[6].  Dessai S, Ninave S, Bele A., 2024, The Rise of remimazolam: A Review of pharmacology, clinical efficacy, and safety profiles. Cureus. 16: e57260. Doi:10.7759/cureus.57260.

[7].  Kilpatrick G. J., 2021, Remimazolam: Non-Clinical and clinical profile of a new sedative/anesthetic agent. Front Pharmacol. 12: 690875. Doi:10.3389/fphar.2021.690875.

[8].  Noor N, Legendre R, Cloutet A, Chitneni A, Varrassi G, Kaye A. D., 2021, A comprehensive review of remimazolam for sedation. Heal Psychol Res.;9: 24514. Doi:10.52965/001c.24514.

[9].  Dao V-A, Schippers F, Stöhr T., 2022, Efficacy of remimazolam versus midazolam for procedural sedation: Post hoc integrated analyses of three phase 3 clinical trials. Endosc Int open. 10: E378–E385. Doi:10.1055/a-1743-1936.

[10]. Dong L, Sun T, Yang J, Zhou Y, Liu X, Liu Z, et al., 2024, Remimazolam has similar anesthetic effect and superior safety compared to propofol in elderly patients: A meta‐analysis of randomized controlled trials. World J Surg. Doi:10.1002/wjs.12273.

[11]. Hoshino R, Ohashi N, Uta D, Ohashi M, Deguchi H, Baba H., 2024, Actions of remimazolam on inhibitory transmission of rat spinal dorsal horn neurons. J Pharmacol Sci. 155: 63–73. Doi: 10.1016/j.jphs.2024.04.002.

[12]. Masui K., 2024, Remimazolam: Its clinical pharmacology and evolving role in anesthesia and sedation practice. Curr Opin Anaesthesiol. 37: 344–351. Doi:10.1097/ACO.0000000000001384.

[13]. Kim, K. M., 2022, Remimazolam: Pharmacological characteristics and clinical applications in anesthesiology. Anesth pain Med. 17: 1–11. Doi:10.17085/apm.21115

[14]. Alharbi K. S, Almalki W. H, Alzarea S. I, Kazmi I, Al-Abbasi F. A, Afzal O, et al., 2024, Anaesthesia-induced changes in genomic expression leading to neurodegeneration. CNS Neurol Disord - Drug Targets. 23: 411–419. Doi:10.2174/1871527322666230508123558.

[15]. Mahmoud M, Mason KP., 2018, Recent advances in intravenous anesthesia and anesthetics. F1000Research. 7: 470. Doi:10.12688/f1000research.13357.1

[16]. Berman H. M, Battistuz T, Bhat T. N, Bluhm W. F, Bourne P. E, Burkhardt K, et al., 2002, The protein data bank. Acta Crystallogr Sect D Biol Crystallogr. 58: 899–907. Doi:10.1107/S0907444902003451.

[17]. Miller P. S, Aricescu A. R., 2014, Crystal structure of a human GABAA receptor. Nature.;512: 270–275. Doi:10.1038/nature13293.

[18]. Zielesny A., 2005, Chemistry software package chemoffice ultra 2005. J Chem Inf Model. 45: 1474–1477. Doi:10.1021/ci050273j.

[19]. Cousins K., 1993, ChemOffice Plus: A package of programs for chemists. J Chem Inf Comput Sci. 33: 788–789. Doi:10.1021/ci00015a603.

[20]. Morris G. M, Huey R, Lindstrom W, Sanner M. F, Belew R. K, Goodsell D. S, et al., 2010, AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 30: 2785–2791. Doi: 10.1002/jcc.21256.AutoDock4

[21]. The PyMOL Molecular Graphics System, Version 2.0, Schrödinger, LLC. 2002. Available: https://pymol.org

[22]. SYSTÈMES D. BIOVIA Discovery Studio. Dassault Syst mes BIOVIA, Discovery Studio Modeling Environment, Release 2017. Dassault Syst mes; 2016. Available: http://accelrys.com/products/collaborative-science/biovia-discovery-studio/

[23]. Pires D. E V., Blundell T. L, Ascher D. B., 2015, pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem. 58: 4066–4072. Doi: 10.1021/acs.jmedchem.5b00104.

[24]. Jia C-Y, Li J-Y, Hao G-F, Yang G-F., 2020, A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discov Today. 25: 248–258. Doi: 10.1016/j.drudis.2019.10.014.

[25]. Kesharwani R. K, Vishwakarma V. K, Keservani R. K, Singh P, Katiyar N, Tripathi S., 2020, Role of ADMET tools in current scenario: Application and limitations. Computer-Aided Drug Design. Singapore: Springer Singapore. pp. 71–87. Doi:10.1007/978-981-15-6815-2_4.