International Journal of Molecular Sciences Review Towards Quantum-Chemical Modeling of the Activity of Anesthetic Compounds Janusz Cukras 1 and Joanna Sadlej 2,* 1 Laboratory of Spectroscopy and Intermolecular Interactions, Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland; [email protected] 2 Faculty of Mathematics and Natural Sciences, Cardinal Stefan Wyszynski University, Wójcickiego 1/3, 01-938 Warsaw, Poland * Correspondence: [email protected] Abstract: The modeling of the activity of anesthetics is a real challenge because of their unique electronic and structural characteristics. Microscopic approaches relevant to the typical features of these systems have been developed based on the advancements in the theory of intermolecular interactions. By stressing the quantum chemical point of view, here, we review the advances in the field highlighting differences and similarities among the chemicals within this group. The binding of the anesthetics to their partners has been analyzed by Symmetry-Adapted Perturbation Theory to provide insight into the nature of the interaction and the modeling of the adducts/complexes allows us to rationalize their anesthetic properties. A new approach in the frame of microtubule concept and the importance of lipid rafts and channels in membranes is also discussed. Keywords: anesthetics; xenon; intermolecular interactions; DFT; molecular dynamics; ONIOM; SAPT; lipid rafts; GABAA; NMDA; Gly; microtubules; TREK-1 Citation: Cukras, J.; Sadlej, J. Towards Quantum-Chemical Modeling of the Activity of 1. Introduction Anesthetic Compounds. Int. J. Mol. The discovery of general anesthesia (GA) is a fundamental achievement for the de- Sci. 2021, 22, 9272. https://doi.org/ velopment of contemporary biochemistry and biomedical science. No precise definition 10.3390/ijms22179272 of GA has been established. Generally, as an answer to the question about anesthesia one can formulate three points: (i) amnesia, (ii) no response to a noxious stimulus and Academic Editor: Bono Lucic (iii) loss of consciousness [1]. In low concentration, the behavioral responses are well known: analgesia, amnesia, excitation, hypnosis and sedation, muscle relaxation, while Received: 15 July 2021 reduced motor and autonomic response in higher concentration of anesthetics [1]. For Accepted: 17 August 2021 Published: 27 August 2021 anesthetics, several criteria have been put forward [2,3]; however, among them the most important is: anesthetics have to produce “a reversible effect at a functional site with Publisher’s Note: MDPI stays neutral clinically relevant concentrations”. with regard to jurisdictional claims in Nowadays, it is still not known how anesthetic molecules cause reversible loss of published maps and institutional affil- consciousness. Neither do we know the mechanism of anesthesia nor how consciousness iations. and memory arise in the brain. Therefore, the research in the field of anesthesia is one of the key paths towards understanding the phenomenon of consciousness [4–9]. Based on recent research it is now generally accepted that anesthetics act in multiple sites, and they modulate the synaptic transmission. However, a comprehensive experimen- tal depiction of such action, e.g., in membrane proteins, is beyond the reach of modern Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. experiment. The docking mechanisms and molecular dynamics (MD) simulations for This article is an open access article anesthetics-protein receptors systems have become the methods of the first choice. MD distributed under the terms and description of trajectories contains useful information, e.g., about dominant conformations conditions of the Creative Commons and average physicochemical properties in a given state. There have been a number of Attribution (CC BY) license (https:// reports suggesting the importance of the intermolecular interactions which play an im- creativecommons.org/licenses/by/ portant role in the stability of proteins interacting with other molecules. This could be a 4.0/). prerequisite to understanding the anesthetic action. Int. J. Mol. Sci. 2021, 22, 9272. https://doi.org/10.3390/ijms22179272 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 20 Int. J. Mol. Sci. 2021, 22, 9272 2 of 20 important role in the stability of proteins interacting with other molecules. This could be a prerequisite to understanding the anesthetic action. AsAs we we have have stressed stressed above, above, the the primary primary event even oft of general general anesthesia anesthesia (GA) (GA) is is the the loss loss ofof consciousness. consciousness. Here, Here, wewe mainlymainly emphasize th thee recent recent progress progress in in the the description description of of the themolecular molecular mechanisms mechanisms of ofGA GA and and the the new new conc conceptsepts of of the the consciousness. consciousness. Studying Studying the theinteractions interactions between between general general anesthetics anesthetics and and th theireir macromolecular macromolecular targets targets is iscrucial crucial to to the theunderstanding understanding of of the the biochemistry biochemistry of of these these drugs. To identifyidentify thethe binding binding sites sites within within targetstargets and and to to determine determine novel novel binding binding molecules molecules within within a givena given biological biological system system is is the the mainmain aim aim of of the the investigations investigations [4 ].[4]. Modern anesthetics are categorized into two main classes which are differentiated Modern anesthetics are categorized into two main classes which are differentiated on on the basis of the method of administration: inhaled (volatile) anesthetics and total the basis of the method of administration: inhaled (volatile) anesthetics and total intrave- intravenous anesthetics (TIVA) [3,4,6]. Inhaled anesthetics are: inorganic gases (nitrous nous anesthetics (TIVA) [3,4,6]. Inhaled anesthetics are: inorganic gases (nitrous oxide, oxide, xenon), multi-halogenated alkanes and ethers (e.g., halothane, sevoflurane (SEVO), xenon), multi-halogenated alkanes and ethers (e.g., halothane, sevoflurane (SEVO), isoflu- isoflurane (ISO)). The halogenated alkanes are a challenge to computational description due rane (ISO)). The halogenated alkanes are a challenge to computational description due to to their unique characteristics as large halogenated compounds. Intravenous anesthetics their unique characteristics as large halogenated compounds. Intravenous anesthetics usually contain more atoms (e.g., propofol and lidocaine) than volatile anesthetics and usually contain more atoms (e.g., propofol and lidocaine) than volatile anesthetics and often have rings and multi-ring functionalities (e.g., ketamine and etomidate). The effect of often have rings and multi-ring functionalities (e.g., ketamine and etomidate). The effect GA is dose-dependent. Most popular GA are presented on Figure1. of GA is dose-dependent. Most popular GA are presented on Figure 1. FigureFigure 1. 1.Structural Structural formulas formulas for for most most important important general general anesthetics. anesthetics. Within the central nervous systems (CNS) anesthetics can have many different targets. The so-called “unitary theory of general anesthesia” was popular in the early period [4] of investigations. According to this concept, general anesthetics act via a common molecular Int. J. Mol. Sci. 2021, 22, 9272 3 of 20 mechanism. At the same time, it was assumed that anesthetics depress neural activity of the CNS by roughly the same amount in all parts of the system. After a large number of experimental findings, however, the hypothesis of common mechanism was abandoned. In this review we summarize recent progress in the understanding of GA, and we pay particular attention to computational methods: the MD simulations and quantum-chemical models which describe intermolecular interactions. The aim of this review is to summarize the last ten years of the computational studies on the anesthetic compounds and to compare, in terms of recently published outputs, the milestones in the development of the GA with the current achievements in elucidating the molecular mechanisms of anesthetic action. We adopt the point of view of molecular interactions theory and phenomenological framework. The review is organized as follows. In order to fully appreciate the issues surrounding the recently published new concept on anesthesia, we continue with a brief presentation of the milestones in the development of the anesthetics in Section2: three relevant approaches known as “lipoid hypothesis”, “protein hypothesis” and “microtubule hypothesis”. We review the general anesthetics group of compounds with special attention paid to highlight the understanding of their exceptional characteristics. Afterwards, Section3 describes shortly the computational methods used. Finally, Section4 is dedicated to a description of the several results of anesthetics research in which computational techniques of classical molecular simulations and quantum-chemical methodology have played important roles, with special emphasis on the role of the intermolecular interactions (analyzed by changing the interacting partners) and the new concepts important to understanding the anesthesia. 2. Milestones in the Development of the Anesthetics: Lipid, Protein and Microtubule Hypothesis in General Anesthesia 2.1. Lipoid Hypothesis The