“The world needs new anesthetic drugs and supportive adjuvants.”

Image: A. Johnson, Vivo Visuals Studio.

Image: A. Johnson, Vivo Visuals Studio.

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The implementation of modern in silico computational chemistry and molecular modeling in this issue of Anesthesiology by Irani et al.1  demonstrates the value that can be brought to our detailed understanding of pharmaceutical mechanisms at a molecular level and how this correlates with clinical effect. The authors stated three goals for their examination of sugammadex interactions with specific drugs: to examine the molecular dynamics of the encapsulation process of rocuronium and vecuronium by sugammadex; to validate the simulation technique by comparing the simulated binding strengths between sugammadex and 11 other compounds with previously published, experimentally obtained affinity data; and to characterize the patterns of sugammadex low-affinity binding with propofol. They showed the pathway by which rocuronium initially aligns itself before strong binding encapsulation via modes involving both a “head-first” approach and a “tail-first” approach. They showed how forming fewer hydrogen bonds produces a lesser affinity for vecuronium. They also showed the log-linear correlation of their relative binding free energy calculations involving mostly enthalpy (the thermal energy of drug binding) with experimental association constants, thereby validating the computational paradigm across several drugs. Finally, they nicely validated the calculated low but nonetheless important binding of propofol by sugammadex through a series of elegant experiments involving hippocampal brain slice electrophysiology.

Modern pharmaceutical development is notorious for costing more than $1 billion and requiring 10 to 12 yr to bring a single drug to market. The process often starts with an idea for a drug target. The “druggability” of the target is assessed for its receptor binding motifs and screened. Once initial drug “hits” are assessed via in vitro target assays, compounds with validated target activity are further modified to optimize desired effects and pharmacokinetics while minimizing off-target effects and toxicities. Animal tests may start with invertebrates, progressing to small and then large mammals. Upon Food and Drug Administration (Silver Spring, Maryland) approval, expensive human trials can ensue through an arduous multiphase process. There are numerous bureaucratic and logistical hurdles throughout. All of this has compounded the high costs and long delays, until now. For the last several years, the application of in silico methodologies at every stage of the drug discovery process has enhanced efficiencies. Software development has taken full advantage of high-end three-dimensional visualization as well as highly parallelized computational algorithms for efficient drug screening (fig. 1). Sophisticated molecular calculations previously only available via supercomputing facilities can now be achieved with advanced desktop workstations, allowing for a greater mechanistic understanding at a molecular level, which can then be leveraged to perform lead refinement toward final drug candidate design. In silico techniques not only allow for more rapid identification of key interactions and prediction of side effects but also can further refine the highly iterative process of drug development from preclinical in vitro studies through human trials.

Fig. 1.

Space-filling three-dimensional atomic model of sugammadex molecule for use in molecular simulations (made using Discovery Studio 2021, Biovia/Dassault Systemes Molecular Modeling Suite, USA).

Fig. 1.

Space-filling three-dimensional atomic model of sugammadex molecule for use in molecular simulations (made using Discovery Studio 2021, Biovia/Dassault Systemes Molecular Modeling Suite, USA).

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Everything is physics, from the subatomic level on up. However, to simulate even some of the most basic biochemical reactions at such fundamental levels using currently available software and hardware would require amounts of time longer than the age of our universe! While many chemical processes can be described using high-level quantum mechanics at very exacting levels for smaller molecular systems, most biochemical interactions involve a larger number of atoms, which makes even approximate quantum chemical calculations intractable. It is in light of this that other methods of molecular modeling were developed using more simplistic yet reasonably accurate methods of calculation. While there are many validated variations of the “forcefields” used to describe such intermolecular and intramolecular interactions that are both commercially available and open-source as implemented by Irani et al.,1  most consist of a series of parameters that have been developed to allow the bond length, bond angle, and bond torsion interactions to be accurately treated using the mathematics of the simple spring potential. These are further supplemented to consider equations involving the interactions between partial atomic charges, as well as hydrophobic interactions through various van der Waals potentials. With the mathematical assessment of atomic interactions in place, the atoms in a system can then be set in motion according to the Newtonian equations from classical physics, with analyses performed using the methods of statistical thermodynamics.2  Together these forcefields form the basis of molecular mechanics and dynamics calculations that are used to understand such complex chemical processes and for which Martin Karplus, Arieh Warshel, and Michael Levitt won the Nobel Prize in 2013. The elegant study by Irani et al. in this issue of Anesthesiology now joins an expanding body of literature that applies molecular simulation techniques to improve our understanding of anesthetic pharmacology3  and novel drug design.4–6 

The world needs new anesthetic drugs and supportive adjuvants. The “miracle of anesthesia” has been enhanced to levels that could never have been imagined since its formal demonstration in 1865, and yet there is so much room for improvement in our pharmaceutical armamentarium. The drug profiles and dangerous side effects of the currently available agents are many, especially among infants7  and the aging geriatric population. Proportionately, the fastest growing segment of the population is octogenarians and older, a group of people who now use the majority of healthcare dollars and are in need of increasing surgical and anesthetic care. With predicted increases in the global anesthetic market to $6.7 billion by 2032, there are both significant clinical pressure and market opportunity to develop new anesthetic agents.8  The improved patient outcomes and cost savings from novel drugs with greater titratability and minimal cardiopulmonary side effects, each of which should lead to shorter and less complicated hospital stays while minimizing overall morbidity and/or mortality, would be substantial. In particular, hypotension and respiratory insufficiencies still occur despite current protocols and remain a costly source of perioperative morbidity and mortality.9–12 

Additionally, an improved safety profile for new agents would increase access to anesthesia by a broader group of practitioners, especially in areas of the world where anesthesia professionals are scarce. The Lancet Commission on Global Surgery concluded that 5 billion of the 7 billion people in the world do not have access to safe, affordable surgical and anesthesia care. While wealthy countries have 20 to 30 anesthesiologists for every 100,000 people, sub-Saharan Africa and parts of Asia often have fewer than 1 for every 100,000 people! The density of trained anesthesia providers is extraordinarily lower in some low-income countries than in most high-income countries, with anesthesia mortality rates correspondingly as much as 1,000 times higher.13 

Overall, the use of new in silico technologies as illustrated by Irani et al.1  can be efficiently implemented not only to improve our understanding of drug–receptor interactions at a molecular level but also to possibly pave the way for a brighter future for our specialty through cheaper, safer drugs. This could allow increased access to the “miracle of anesthesia” for an even larger and more diverse group of ill patients throughout both developed and underdeveloped countries and should be one of the major research goals within our specialty.

Dr. Bertaccini is supported by a Stanford University School of Medicine Department of Anesthesia FIDL grant (Stanford, California), a Stanford University School of Medicine SPARK Scholar Grant, and the United States Department of Veterans Affairs at the Palo Alto VA Health Care System, (Palo Alto, California).

Dr. Bertaccini is an inventor on U.S. patent No. 10,513,494 B2, “Methods, Compounds, and Compositions for Anesthesia.”

1.
Irani
AH
,
Voss
L
,
Whittle
N
,
Sleigh
JW
:
Encapsulation dynamics of neuromuscular blocking drugs by sugammadex.
Anesthesiology
2023
;
138
:
152
63
2.
Leach
AR
:
Molecular Modelling: Principles and Applications
, 2nd edition.
Essex, United Kingdom, Pearson
,
2001
3.
Oakes
V
,
Domene
C
:
Capturing the molecular mechanism of anesthetic action by simulation methods.
Chem Rev
2019
;
119
:
5998
6014
4.
Sear
JW
:
Challenges of bringing a new sedative to market!
Curr Opin Anaesthesiol
2018
;
31
:
423
30
5.
Cayla
NS
,
Dagne
BA
,
Wu
Y
,
Lu
Y
,
Rodriguez
L
,
Davies
DL
,
Gross
ER
,
Heifets
BD
,
Davies
MF
,
MacIver
MB
,
Bertaccini
EJ
:
A newly developed anesthetic based on a unique chemical core.
Proc Natl Acad Sci USA
2019
;
116
:
15706
15
6.
Hu
Y
,
Li
X
,
Liu
J
,
Chen
H
,
Zheng
W
,
Zhang
H
,
Wu
M
,
Li
C
,
Zhu
X
,
Lou
J
,
Yan
P
,
Wu
N
,
Liu
X
,
Ma
S
,
Wang
X
,
Ding
Y
,
Xuan
C
:
Safety, pharmacokinetics and pharmacodynamics of a novel gamma-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment.
Ann Med
2022
;
54
:
2769
80
7.
Useinovic
N
,
Jevtovic-Todorovic
V
:
Novel anesthetics in pediatric practice: Is it time?
Curr Opin Anaesthesiol
2022
;
35
:
425
35
8.
General anesthesia drugs market snapshot (2022-2032).
.
9.
Sessler
DI
,
Meyhoff
CS
,
Zimmerman
NM
,
Mao
G
,
Leslie
K
,
Vasquez
SM
,
Balaji
P
,
Alvarez-Garcia
J
,
Cavalcanti
AB
,
Parlow
JL
,
Rahate
PV
,
Seeberger
MD
,
Gossetti
B
,
Walker
SA
,
Premchand
RK
,
Dahl
RM
,
Duceppe
E
,
Rodseth
R
,
Botto
F
,
Devereaux
PJ
:
Period-dependent associations between hypotension during and for four days after noncardiac surgery and a composite of myocardial infarction and death: A substudy of the POISE-2 trial.
Anesthesiology
2018
;
128
:
317
27
10.
Roshanov
PS
,
Sheth
T
,
Duceppe
E
,
Tandon
V
,
Bessissow
A
,
Chan
MTV
,
Butler
C
,
Chow
BJW
,
Khan
JS
,
Devereaux
PJ
:
Relationship between perioperative hypotension and perioperative cardiovascular events in patients with coronary artery disease undergoing major noncardiac surgery.
Anesthesiology
2019
;
130
:
756
66
11.
Mathis
MR
,
Naik
BI
,
Freundlich
RE
,
Shanks
AM
,
Heung
M
,
Kim
M
,
Burns
ML
,
Colquhoun
DA
,
Rangrass
G
,
Janda
A
,
Engoren
MC
,
Saager
L
,
Tremper
KK
,
Kheterpal
S
,
Aziz
MF
,
Coffman
T
,
Durieux
ME
,
Levy
WJ
,
Schonberger
RB
,
Soto
R
,
Wilczak
J
,
Berman
MF
,
Berris
J
,
Biggs
DA
,
Coles
P
,
Craft
RM
,
Cummings
KC
,
Ellis
TA
, 2nd
,
Fleishut
PM
,
Helsten
DL
,
Jameson
LC
,
van Klei
WA
,
Kooij
F
,
LaGorio
J
,
Lins
S
,
Miller
SA
,
Molina
S
,
Nair
B
,
Paganelli
WC
,
Peterson
W
,
Tom
S
,
Wanderer
JP
,
Wedeven
C
;
Multicenter Perioperative Outcomes Group InvestigatorsMulticenter Perioperative Outcomes Group Investigators
:
Preoperative risk and the association between hypotension and postoperative acute kidney injury.
Anesthesiology
2020
;
132
:
461
75
12.
Huber
M
,
Ozrazgat-Baslanti
T
,
Thottakkara
P
,
Efron
PA
,
Feezor
R
,
Hobson
C
,
Bihorac
A
:
Mortality and cost of acute and chronic kidney disease after vascular surgery.
Ann Vasc Surg
2016
;
30
:
72
81.e1
13.
Barreiro
G
,
Mellin-Olsen
J
,
Gore-Booth
J
:
The role of the WFSA in reaching the goals of the Lancet Commission on Global Surgery.
Anesth Analg
2018
;
126
:
1400
4