Skip to Main content

Journals & booksRegisterSign in

Structure Activity Relationship
Structure–activity relationships (SARs) are models that attempt to
extrapolate from the center of the onion, i.e., the chemical structure, to
different types of biological endpoints.
From: Comprehensive Medicinal Chemistry II, 2007
Related terms:
 Alkaloid
 G protein-coupled receptor
 Peptide
 Toluene
 Small molecule
 Agonist
 Binding site
 N-terminus
 Antibiotics
 Apoptosis
Learn more about Structure Activity Relationship
26RFa
Jérôme Leprince, ... Hubert Vaudry, in Handbook of Biologically Active
Peptides (Second Edition), 2013
Structure–Activity Relationships
Structure–activity relationships of 26RFa have been assessed by
measuring the Ca2+-mobilizing activity of human 26RFa-related
analogs in hGPR103-transfected CHO cells. Peptide truncation
studies indicate that the biologically active domain of 26RFa is located
in the C-terminal region and that 26RFa(20–26) is the shortest analog that
retains full efficacy to increase [Ca2+]i in GPR103-transfected
cells.16 Systematic replacement of each amino acid of 26RFa(20–26) by
an alanine (Ala scan) or its D-enantiomer (D scan) shows that the last
three C-terminal residues are very sensitive to these modifications
while position 23 tolerates both substitutions rather well.16 Most
importantly, replacement of Ser23 by a norvaline leads to an analog,
[Nva23]26RFa(20–26), which is 3-fold more potent than the native
heptapeptide.16
Read full chapter
Chemical Ecology
Isomaro Yamaguchi, ... Yoji Sakagami, in Comprehensive Natural
Products II, 2010
4.02.6.2.5
Structure–activity relationship
Structure–activity relationships have already been
reviewed.737,738,766 The structure–activity relationships of BRs have been
investigated using bean, rice, tomato, and radish with the first two
being frequently used.766 The bean bioassay to examine the elongation
of the second internodes, used in the early stage of researches, is
very sensitive to structural changes.767 For example, loss of the methyl
group at C24 nearly abolishes the biological activity. Brassinolide is
100-fold more active than castasterone although both are known to be
biologically active on their own. The overall structural requirements of
BRs with trans-A/B ring system are 2α,3α-vicinal diol in A ring, 7-oxa-
6-one (lactone) in B ring, as well as 22R,23R- or 22S,23S-diol and 24-
methyl in the side chain.
The rice bioassay to examine the promotive effect of BRs on the
lamina inclination has been extensively utilized.768,769 This bioassay is
affected to a lesser extent by structural variations than the bean test
is. For example, castasterone is fourfold less active than brassinolide,
this being in good correlation with their binding abilities to the receptor
BRI1. Favorable functionalities are 2α,3α-vicinal diol or 3α,4α-vicinal
diol in A ring, 7-oxa-6-one or 6-ketone in B ring, as well as methyl,
ethyl, methylene, or ethylidene at C-24, or an additional methyl group
at C-25 (terminal tertiary butyl group) in the side chain.766 Among
naturally occurring BRs, brassinolide is the most biologically active
except that 25-methylbrassinolide found only in Phaseolusseeds
shows higher activity.770 The effects of substituents at C-14, C-25, C-
26, and C-28 were further examined, revealing that introduction of
functional groups such as hydroxyl and halogen into these carbons
reduced the biological activity771–773 although the presence of a methoxy
group at C-25 increased the biological activity.771 The requirement of
the trans-A/B ring system for the biological activity was rigorously
confirmed by a new synthetic approach.774,775
Read full chapter
Software Tools for Toxicology and Risk Assessment
Charles Pittinger, Asish Mohapatra, in Information Resources in
Toxicology (Fourth Edition), 2009
QSAR Tools
Structure–activity relationships (SARs) and quantitative structure–
activity relationships (QSARs) are theoretical models that can be used
to predict the physicochemical, biological, and environmental
properties of substances. A SAR is an (qualitative) association
between a chemical substructure and the potential of a chemical
containing the substructure to exhibit a certain biological property or
effect. A QSAR is a mathematical model that quantitatively relates a
quantitative numerical measure of chemical structure (e.g., a physico-
chemical property) to a physical property or to a biological effect (e.g.,
a toxicological endpoint).
QSARs are tools commonly used in the absence of available data for
prioritization, classification, and screening level risk assessment. A
broad range of QSAR models can readily fill data gaps for assessing
chemicals, particularly for fundamental physical–chemical properties,
in an expedient and cost-effective manner. QSAR-based evaluations
can provide a systematic and consistent approach to chemical
evaluations involving large numbers of chemicals. Certain (Q)SARs
and other types of theoretical models have gained broad acceptance
by regulatory institutions and the private sector. Predictive models can
reduce costs, time, and concerns related to conducting toxicity
bioassays. Input data requirements are generally modest and
increasingly available through public and computerized databases.
Read full chapter
Nesfatin-1
Andreas Stengel, Yvette Taché, in Handbook of Biologically Active
Peptides (Second Edition), 2013
Receptors and Signaling Cascades
Structure activity relationship studies indicate that full length NUCB2
as well as nesfatin-1 exerts an anorexigenic effect after injection into
the brain ventricle while nesfatin-2 and nesfatin-3 do not.22 Several
fragments of nesfatin-1, namely N-terminal nesfatin-11–29, the mid-
fragment nesfatin-130–59 and the C-terminal nesfatin-160–82 (Fig. 1B) were
also synthesized based on structural analysis of the α-helix of
nesfatin-1 and tested for biological activity. Only the mid fragment is
able to reproduce the anorexigenic effect of nesfatin-1 after peripheral
injection in mice suggesting that this fragment may contain the active
core of the peptide interacting with the receptor.26 However, it remains
to be established whether nesfatin-130–59 is generated in vivo.
Still to be identified is the receptor to which nesfatin-1 binds. One
study showed that nesfatin-1 interacts with a receptor that has
pharmacological characteristics of G protein-coupled receptors. This
was based on in vitro results in cultured rat hypothalamic neurons
showing that nesfatin-1 induces a fast rise in [Ca2+]i which is abolished
by pertussis toxin, indicating the involvement of a Gi/o protein-coupled
receptor and is also reduced by a specific protein kinase A inhibitor
indicative of a role of protein kinase signaling.8 The identification and
consecutive pharmacological characterization of the nesfatin-1
receptor will represent an important leap forward to better understand
nesfatin-1 signaling and physiology.
Read full chapter
Nociceptin Opioid
Rink-Jan Lohman1, ... David P. Fairlie2, in Vitamins & Hormones, 2015
6.1
Design of helix-constrained nociceptin analogues
Structure–activity relationship studies involving peptide truncations, as
well as alanine and d-residue scanning have revealed that the
message sequence is very sensitive to substitution with changes to
Phe1, Gly2, and Phe4 resulting in complete loss of activity. The
address domain (residues 7–17) is less sensitive to substitution, but
replacing Arg8 abolished activity. Modifying the N-terminal Phe1
residue to N-benzyl-glycine (BzlGly) conferred a functional shift from
agonist to pure antagonist activity (Calo, Guerrini, et al., 2000;
Guerrini, Calo, Bigoni, Rizzi, Rizzi, et al., 2001). The available NMR
structure in sodium dodecyl sulfate solution suggests that residues 4–
17 may have some helical propensity, whereas in water the N-terminal
pentapeptide appeared to be significantly more flexible and is not
likely to be helical. Three nociceptin analogues, each containing two
lactam bridges with different spacing, have recently been studied.
These contain (1) back-to-back, (2) separated, or (3) overlapping
lactam bridges (Fig. 7). In all strategies, critical residues Phe1, Phe4,
and Arg8 are conserved. Due to the lack of three-dimensional
structural information for the ORL-1 receptor in complex with
nociceptin, it is uncertain whether the introduction of lactam bridges
would interfere with receptor binding, so all three approaches for helix
constraints were utilized in synthesized peptides. Based on the
literature, conversion of the cyclic agonists to antagonists was
expected to be possible by removing the N-terminal message domain
or replacing the N-terminal phenylalanine (Phe1) with N-benzyl-
glycine (BzlGly1). It was also expected that these changes would
improve the potency of cyclic agonist and antagonist peptides by
making Phe4(pF)Phe, Leu14Arg, and Ala15Lys substitutions
previously reported in the literature (Fig. 5).
Compounds 1–23 (Table 3) were synthesized using solid-phase
techniques. Peptide concentration was assessed using absorbance
at λ = 258 nm or an NMR method called PULCON (Wider & Dreier,
2006; Table 3). The presence of chromophores pF(Phe) or BzlGly
altered the emission spectrum at 258 nm, requiring assessment of
peptide concentration by NMR methods.
Read full chapter
Protein Prenylation PART A
Masahiro Okadaa, ... Youji Sakagamib, in The Enzymes, 2011
VI
Structure–Activity Relationships of ComXRO-E-2Pheromone
Structure–activity relationship studies on ComXRO-E-2pheromone were
carried out by using synthetic alanine-substituted ComXRO-E-
2 derivatives. All amino acid residues of ComX RO-E-2 pheromone, with

the exception of the geranylated tryptophan residue, can be replaced

by alanine without significant reduction of activity (Table 10.1).
Addition of alanine residues on both the N- and C-terminal does not
affect the biological activity and both the N- and C-terminal residues
are dispensable. Presently, the smallest functional peptide that has
been identified is a tripeptide, F-W(modified)-E (Table 10.1) [35].
These studies have demonstrated that the geranylated tryptophan
residue is an essential role for expressing biological activity.
We synthesized six geranylated tryptophans, which geranyl group
substitutes 1-, 2-, 4-, 5-, 6-, and 7-position of hydrogen on indole ring,
and using these geranylated tryptophans, hexapeptides were
synthesized with the same amino acid sequence as ComXRO-E-
2 pheromone [36]. But, all peptides synthesized did not show any

activity. Thus, the geranyl side chain of peptide does not have only the
role to addition of lipophilicity to the peptide, but the typical tricyclic
structure is essential to biological activity. The newly formed five-
membered ring in the modified tryptophan residue is resembled to
proline. Since proline is well known as a key amino acid residue to
define the three-dimensional structure of protein, it will be possible
that the modified tryptophan residue strongly affects the conformation
of ComX pheromone. When we determined the chemical structure of
ComXRO-E-2 pheromone, we determined the direction of geranyl side
chain and the proton at 2-position of an original indole ring in the same
side of rings with the NOE data of NMR [23,24]. The absolute
stereochemistry was elucidated by computer simulation using coupling
constant comparing with model compounds. To confirm the proposed
structure, we synthesized four stereoisomers of geranylated
tryptophan, which had stereochemistry of Lα, Lβ, Dα, and Dβ. Only
the peptide having Lα geranyl tryptophan residue showed biological
activity and other three isomers showed no activity [23]. These results
indicate that the stereochemistry of geranylated tryptophan is also
essential expressing the activity, and in other word, the receptor of
ComXRO-E-2 pheromone, ComPRO-E-2, can recognize the exact
stereochemistry of modified tryptophan residue.
In contrast, earlier work on the structure–activity relationships of
tremerogen A-10, which is the sex pheromone of basidiomycetous
yeast and contains an S-farnesyl-modified cysteine residue, revealed
that removal of the N-terminal residues induced loss of biological
activity [37]. Replacement of the farnesyl group with an alkyl chain had
no significant effect on the biological activity of tremerogen A-10;
moreover, replacement with a longer isoprenoid caused an increase in
activity. The activity spectrum of tremerogen A-10 strongly contrasts
with those of ComX pheromones. These results also indicate that the
pattern of specific interaction of the ComX pheromone with its receptor
is unique from that of the S-isoprenoidal peptide pheromone.
The two isoprenoidal groups may also influence the species (or
group)-specific bioactivity exhibited by ComX pheromones.
Experiments utilizing conditioned media of producer strains and
partially purified ComX variants have revealed a correlation between
specific activation pattern and type of modifying isoprenoid (Figure
10.6) [19–22]. In fact, synthetic ComX pheromone modified with a
farnesyl group showed significant activity in strains that produce
farnesylated ComX, but had little activity in strains that produce
geranylated pheromone, and vice versa (unpublished data). Since
geranyl- and farnesyl-modified tryptophan residues have identical core
structures that differ only in side-chain length, the length of the
isoprenyl side chain appears to be a more influential determinant of
group specificity than the amino acid sequence of the pheromone. The
geranyl and farnesyl moieties in modified ComX pheromone are
directly involved in ligand-receptor interactions. Interestingly, N-acyl-
homoserine lactones, Gram-negative bacterial quorum-sensing
pheromones, also have group-specific activity that is influenced by the
length of the acyl side chain [2–4]. As quorum-sensing signal
receptors have binding pockets precisely adapted to the length of the
target acyl chain [38], bacilli may have evolved the isoprenoidal moiety
in ComX pheromones to fit their own receptor, ComP, in a similar
manner.
Read full chapter
Redox and Cancer Part A
Olof Modén*, Bengt Mannervik*†1, in Advances in Cancer
Research, 2014
7.1
Chimeric GST variants obtained by DNA shuffling of homologous sequences
Structure–activity relationships were sought in order to understand the
higher catalytic efficiency of human GST A2-2 compared to the other
GSTs examined. DNA shuffling (Stemmer, 1994) of the coding
sequence of GST A2-2 with homologous alpha class GSTs generated
a library of related GST chimeras that could be heterologously
expressed and characterized (Kurtovic, Modén, Shokeer, &
Mannervik, 2008). Three human GSTs, A1-1, A2-2 (allelic variant
A*C), and A3-3, and bovine GST A1-1 and rat GSTs A2-2 and A3-3
were used for the construction of the library. The latter three
mammalian sequences added increased structural diversity to the
chimeras. Human GST A2-2 shares 95% amino acid sequence
identity with human GST A1-1, 89% with human GST A3-3, 81% with
bovine GST A1-1, 73% with rat GST A2-2, and rat GST A3-3.
Between themselves, these two rat GST sequences are not more than
68% identical. By including enzymes with larger sequence divergence
and with both high and low activity toward azathioprine, the regions of
importance for the function could be identified. Only human GSTs A1-
1 and A2-2 have relatively high azathioprine activity.
To introduce additional variability, a previously created mutant library
of human GST A1-1 was included in the shuffling. This library had 10
potential H-site residues mutated with the degenerate codon NNN to
encode all 20 amino acids (Hansson, Widersten, & Mannervik, 1997;
Widersten & Mannervik, 1995). Point mutations in the active site have
probably a higher chance of drastically altering the function of the
enzyme compared to mutations further away. Shuffling of homologous
sequences introduces mutations in block-wise segments and affects
both the active site and more distant parts of the enzymes. Human
GST A4-4 had too low sequence identity with human GST A2-2 (54%)
to be included in the shuffling process (Hubatsch, Ridderström, &
Mannervik, 1998). The fifth human alpha class gene encoding GST
A5-5 can be processed to a mature mRNA, which is translation-
competent, producing a catalytically active enzyme (Singh, Zimniak, &
Zimniak, 2010), but the protein has not so far been identified in vivo.
The H-site residues of GST A5-5 are highly similar to those of GST
A2-2, but the G-site substitution R15S in human GST A5-5 might be
detrimental to the catalytic activity, considering the conservation of a
basic residue in this position and its importance for catalysis in alpha
class sequences (Björnestedt et al., 1995; Dourado, Fernandes,
Mannervik, & Ramos, 2010). For these reasons, GSTs A4-4 and A5-5
were not included in the chimeragenesis.
Read full chapter
Amino Acids, Peptides and Proteins
Jason Kindrachuk, ... R.E.W. Hancock, in Comprehensive Natural
Products II, 2010
5.07.6
Structure–Activity Relationship Studies of the Antimicrobial Activities of the
Host Defense Peptides
Structure–activity relationship studies investigating the antimicrobial
activities of host defense peptides have primarily sought the
characterization of the specific sequence/structural motifs that dictate
antimicrobial and cytotoxic activities. Perhaps unsurprisingly these
activities appear to be dictated by a delicate balance of cationicity,
hydrophobicity, amphipathicity, and ultimately the structural
characteristics of the peptides.
The effect of increased cationicity on cytotoxicity and antimicrobial
activity has been investigated in magainin II. Dathe et al.108 have
demonstrated that increased cationicity in magainin results in an
increased hemolytic propensity and concomitant loss of antimicrobial
activity. Magainin II derivatives comprising overall cationic charges
ranging from +3 to +7 were constructed and it was demonstrated that
antimicrobial activity could be increased when overall charge was
increased to a threshold of +5; however, charges above +5 resulted in
a loss of antimicrobial activity. Importantly, the correlation between the
maintenance of overall peptide hydrophobicity with optimized activity
supports the existence of a delicate balance between hydrophobicity
and cationicity within host defense peptides. The authors note that the
loss in activity above the threshold charge of +5 likely represents
reduced helicity within the peptides or excessive electrostatic
interactions between the cationic peptides and the anionic
phospholipid head groups. The relationship between peptide
amphipathicity and antimicrobial activity has also been investigated
using the cyclic β-sheet antimicrobial peptide gramicidin S, a peptide
with high permeabilization activity toward neutral membranes. Lee et
al.86 have modified peptide amphipathicity while maintaining sequence,
charge, and intrinsic hydrophobicity. Decreased peptide
amphipathicity using diastereomeric substitutions (d- and l-amino
acids) resulted in increased antimicrobial activity and decreased
hemolytic activity.
Earlier investigations have indicated that the network of disulfide
linkages found within β-defensins is not required for antimicrobial
activity.109 An investigation by Klüver et al.110 has demonstrated that
disulfide connectivity in a particular context is not required for
antimicrobial activity. Indeed, HBD-3 derivatives lacking disulfide
bonds were found to be as active as their cyclic analogues. This is in
agreement with a previous study by Hoover et al.111 in which a linear
variant of full-length HBD-3 retained antimicrobial activity against a
broad range of organisms. Interestingly, the authors also demonstrate
that the antimicrobial activity of the peptide was dependent on overall
cationicity as linear derivatives of the C-terminus, which houses the
antimicrobial domain of the peptide, showed increasing antimicrobial
activities that correlated with increasing basicity of the peptides.
Derivatives of HBD-3 with Trp substitutions at the N-terminus also
increased antimicrobial activity. This is perhaps unsurprising as
previous studies of the Trp-rich peptides such as lactoferricin112 and
indolicidin113 have identified the necessity of this amino acid for
antimicrobial activity.
Tryptophan residues have been demonstrated to facilitate the most
stable associations between peptides and membranes of all the amino
acids. Trp residues are able to form hydrogen bonds with both water
and lipid bilayer components upon imbedding into the interfacial
region and as well as disrupt the strong hydrophobic interactions
between the lipid acyl chains.114 As a testament to the importance of
Trp residues within antimicrobial peptides, it has been demonstrated
that a parallel arrangement between Arg and Trp residues does not
impede the formation of hydrogen bonds between water molecules
and the Arg side chain.114 As Arg and Trp residues are found in high
proportions within many host defense peptides, it would be anticipated
that interactions between these two molecules would occur. In
contrast to Arg, Lys residues cannot hydrogen bond while in cation–π
interactions with aromatic amino acids and this difference is likely
responsible for the increased antimicrobial activity of Arg-rich peptides
over their Lys variants.114
As many natural host defense peptides exhibit toxicity to host cells, it
is prudent to investigate the characteristics that define cell selectivity
between microbes and host cells as this will aid in the development of
synthetic peptides with optimized activities. Melittin, a 26-residue
antimicrobial peptide found within bee venom, has strong antimicrobial
and cytolytic activities.115Indeed, structure–function studies have
sought to define the molecular mechanisms behind the poor cell
selectivity of the peptide. The three-dimensional structure of melittin
indicates a tetrameric helix-bend-helix structure with the first helix
encompassing residues 1–10, the second between residues 13–26,
and a short bend region within residues 11–12.116 Mutation of the first
20 amino acids with an alternative helix-forming sequence had little
effect on either the cytolytic or antimicrobial activities of the peptide
indicating a central importance of the helix to both activities. 117 Further,
the individual deletion of residues Leu-6, Lys-7, Val-8, Leu-9, Leu-13,
Leu-16, Ile-17, Trp-19, and Ile-20 resulted in the significantly reduced
cytotoxicity of the peptide and, to a lesser extent, antimicrobial
activity.118Recently, Asthana et al.119 have demonstrated the presence
of a leucine zipper motif between residues 6 and 20 of melittin.
Interestingly, replacement of heptadic leucine with single- or double
alanine resulted in significant reduction to the hemolytic activity of the
peptide; however, antimicrobial activity was comparable to the
unmodified peptide for both mutants. The authors noted that the
membrane permeability of the analogues contrasted between neutral
and negatively charged membranes and that this likely reflects
different mechanisms of action for the peptides in the two
environments. It was also noted that the substitutions of leucine to
alanine in melittin decreased the ability of the peptide to self-associate
and was postulated that self-association is required for the partitioning
of peptides into the cell membrane and eventual lysis.119 The
requirement of peptide self-association for hemolytic activity has also
been demonstrated for other host defense peptides. Truncation of LL-
37 has been demonstrated to reduce both hemolytic activity and
oligomerization capability without affecting antimicrobial
activity.120 Interestingly, d-amino acid substitutions within host defense
peptides have been demonstrated to reduce peptide oligomerization
and hemolytic activities.121 Although there has been little mechanistic
evidence to explain this phenomenon, it is likely that the reduced
potential for d-amino-substituted peptides to self-associate results in
reduced hemolytic activity. In support of this postulate, the correlation
between reduced overall hydrophobicity and hemolytic activity also
likely results from a decreased oligomerization propensity.
Structure–activity relationship studies of host defense peptide
antimicrobial activities have also extended beyond the spectrum of
natural peptides. A recent investigation by Zelezetsky and
Tossi122 describes a methodology for the design of optimized α-helical
peptides with optimized antimicrobial activity based on sequence
patterns from natural host defense peptides. Through the analysis of
150 peptide sequences of varying length, it was found that most
natural peptides contain the following: net charge range of +4 to +9,
40–60% hydrophobic residues, and a relative amphipathicity of 50–
60% optimal. Interestingly, the authors conclude that antimicrobial
activity is related to overall cationicity rather than a particular
sequence context or motif. It has also been demonstrated that helical
structuring of antimicrobial peptides is indicative of cytotoxic or
antimicrobial activities; indeed, peptides that were less prone to
structure maintained moderate antimicrobial activity with significantly
decreased toxicity.123 Dathe et al.124 also have demonstrated using a
series of variants of the idealized amphipathic α-helical peptide
KLALKLALKALKAAKLA-NH2. Reductions to overall peptide helicity as
a consequence of substitutions within the middle region of the peptide
led to marked reduction in hemolytic activities but only moderately
affected antimicrobial activity. It would be anticipated that this disparity
in activities is the result of the differences between host and microbial
cell membranes such that the initial electrostatic interaction between
the peptide and bacterial cell membrane would be unaffected by
changes to helicity, whereas the ability to fold into an amphipathic
conformation likely drives the insertion of peptides into host cell
membranes.1
Thus, the optimization of the antimicrobial activity and minimization of
cytotoxicity associated with host defense peptides through natural or
synthetic means require the balance of a variety of physicochemical
properties rather than the optimization of a single attribute.
Read full chapter
Neuromuscular Blockers and Reversal Drugs
Cynthia A. Lien, Matthias Eikermann, in Pharmacology and
Physiology for Anesthesia, 2013
Neuromuscular Blocking Activity
Structure-activity relationships of NMBAs can affect neuromuscular
blocking activity, pharmacokinetic properties, and side effect profiles.
Since the early classification of NMBAs as rigid bulky molecules with
amine functions incorporated into ring structures, much has changed
in modern understanding of the relationships between their structures
and function as neuromuscular blockers.32
The postjunctional nicotinic acetylcholine receptor is a pentameric
member of the superfamily of ligand-gated ion channels. This mature
form consists of five subunits: two alpha (α), one delta (δ), one beta
(β), and one epsilon (ε) (Figure 19-3). In the immature (fetal) form, the
ε subunit is replaced by a gamma (γ) subunit. The N- and C-terminal
ends of each subunit are extracellular, with the protein transversing
the lipid bilayer membrane four times, creating four transmembrane
domains (M1, M2, M3, and M4). The M2 domain of each subunit
creates the central ion pore (see Figure 19-3).
The agonist binding sites of the acetylcholine receptor are located at
the interface of the α-δ and α-ε subunits where the N-terminus of each
subunit interacts with that of the other to form the acetylcholine
binding site. In order for the central pore of the receptor to open,
allowing for influx of Na+ and Ca2+ and efflux of K+, two agonist
molecules must be bound to the receptor. The two binding sites are
not identical (the δ-subunit contributes to one receptor and the ε-
subunit contributes to the other). These differences lead to varying
affinity at each of the sites for agonists and competitive antagonists.33-
35 The fetal α-γ binding site is generally more sensitive than the mature

α-ε one.35 The α-γ binding site has up to a 500-fold greater affinity for
d-tubocurarine than does the α-δ binding site.36 In mature receptors,
the α-δ binding site appears to be more important than the α-ε site in
determining receptor affinity for pancuronium, vecuronium, and
cisatracurium. It does not appear to play a significant role in
determining the sensitivity to either metocurine or d-tubocurarine.37
The complexity of fitting large molecules, such as neuromuscular
blocking agents, into acetylcholine receptor agonist binding sites
(Figure 19-4) implies that conformational changes in the NMBA are
required.38 While these compounds are large, they can bend and fold
and will seek a conformation requiring minimal energy. Interaction of
the γTyr117 with the 2-N and 13′ positions of d-tubocurarine suggests
that allosteric changes in either the antagonist or receptor occur with
binding.39 Several different sites of interaction in the binding site are
involved in binding the agonist or antagonist.39 Different affinities at
each of these sites might account for some of the synergism observed
when different NMBAs are administered to the same patient.40
In addition to opening of the ion channel of postjunctional
acetylcholine receptors, neuromuscular transmission is modulated by
a population of prejunctional cholinergic receptors. These
prejunctional nicotinic and muscarinic receptors on the motor nerve
endings are involved in the modulation of the release of acetylcholine
into the neuromuscular junction. Prejunctional nicotinic receptors are
activated by acetylcholine and function in a positive feedback control
system that serves to maintain the availability of acetylcholine when
demand is high. They are involved in mobilization of synaptic vesicles
containing acetylcholine toward the release sites in the presynaptic
membrane of the motor nerve terminal, but not the actual process of
acetylcholine release. These receptors are morphologically different
than those at the postjunctional membrane and consist of three α
subunits and two β subunits. All NMBAs tested, including mivacurium,
atracurium, cisatracurium, d-tubocurarine, pancuronium, rocuronium,
and vecuronium, inhibit presynaptic nicotinic acetylcholine receptors in
a concentration-dependent fashion with concentrations causing 50%
inhibition of response (IC50) in the micromolar range.41 Vecuronium and
d-tubocurarine are the most potent inhibitors of this receptor subtype,
and mivacurium the least potent. Inhibition of this presynaptic receptor
by NMBAs is primarily competitive, but d-tubocurarine and vecuronium
also produce noncompetitive inhibition. The effects of blockade on
these presynaptic receptors during periods of stress, such as TOF or
tetanic stimulation likely accounts for the fade observed in the TOF
response with small doses of NMBA, such as those administered
before succinylcholine to decrease the incidence and severity of
fasciculations of NMBAs.42,43
Read full chapter
The Significance of Discovery Screening and Structure
Optimization Studies
Odilia Osakwe, in Social Aspects of Drug Discovery, Development
and Commercialization, 2016
5.3.3
Structure–Activity Relationship in Drug Discovery
Structure–activity relationships (SAR) explore the relationship
between a molecule’s biological activity and the three-dimensional
structure of the molecule; computational chemistry is employed only if
the target structure is known. Structural-aided drug design uses
crystal structures in the design of molecules. It is often used as an
adjunct to other screening strategies within big pharma. A compound
is docked into the crystal in order to use it to predict where
modifications could be added to provide increased potency or
selectivity.
Since the early 1980s drug discovery has principally relied on a target
protein’s structure to aid drug design. One outstanding strategy is
design of compounds through design-make-test-analyze involving
expert designers from varied pharmaceutical disciplines that interact
to simplify the process of a candidate compound that is taken to the
synthetic routes. This involves medicinal, computational, synthetic,
and physical chemists and also pharmacokinetics (PK) experts on
each project [48–50]. Molecular modeling software packages are often
useful to identify binding site interactions, but when there is no
previous knowledge of the target structure, traditional
noncomputational methods of studying SARs are employed.
Drug molecules typically contain several functional groups, which can
interact with certain groups in the biological target. The biological
targets respond to compound properties and not structure but have to
be determined by downstream process for clinical applications.
Structure-based computer-aided drug design (SBCADD) is a
promising approach in analyzing 3D structures of biologic molecules.
The operating principle of SBCADD is based on the notion that a
molecule could interact with a specific protein and exert a desired
biologic effect, which essentially relies on its ability to favorably
interact with a particular binding site on that protein and that any
molecule with this ability could exert similar biologic effects. This has
allowed elucidation of novel compounds based on their interaction
potential with the protein’s binding site. Structural information about
the target is a prerequisite for any SBCADD project.
Computational tools offer the opportunity to exploit a database
containing new, potential compounds, predicted using QSAR models.
A combinatorial approach to constructing chemical libraries results in
a chemical space different from that of known drugs and natural
products. Because of this, QSAR has been useful in guiding the
combinatorial library synthesis for libraries that could be screened for
targeted drug classes allowing a wide coverage of chemical space
with more likely targeted hits [51].
Pharmaceutical researchers use 3D structural techniques such as
protein docking and pharmacophore similarity to specify similar
biological activities. An enhanced feature of this permits actual
visualization of results – compounds can be viewed docked into the
protein structure. This enables adequate selection of highly promising
compounds that exhibit favorable protein docking and hence potency.
Different structures can act at the same biological target to elicit the
same biological action, but the chemical structures, which are mostly
atoms separated by bonds, are not what is recognized by a biological
target. Two molecules devoid of any structural relationship to one
other could mimic each other in occupying the same site on a
common target but could exhibit very diverse activities at the target.
The electrostatic fields are dynamic and change with the orientation or
shape of the drug compound and this resultant electrostatic field that
aligns with that of the protein target is the reason for target-drug
selectivity [52]. The results of SAR studies can provide information on
the intermolecular interactions that are established at the binding site.
5.3.3.1 Limitations of SAR Application
Increasing sophistication in drug discovery tools and technologies has
still not completely resolved the most crucial need; the preclinical
ADME (absorption, distribution, metabolism, and excretion), safety,
and toxicity problems that consequently either fail to meet Food and
Drug Administration (FDA) approval, or lead to unanticipated health
issues while in the market. ADME prediction with the available models
has been an arduous task but when not predictive enough, could, at
least, guide the drug developer into safer chemical space [53].
For example, it has become a challenge for the chemist to build a
chemotype due to the uncertain probability of success since the
structural features do not give precise information about compound
activity or all the required attributes of a candidate drug [52]. This
obviously requires a huge investment, which might be lost if no
alternative viable chemotypes are found. Individual (Q)SAR in
silico toxicological methods do not consider dose and exposure,
unless the exposure–response relationship is part of the study.
Therefore, it predicts toxicity independently. For example, the aromatic
nitro group that triggers a structural alert for carcinogenicity may pass
undetected if this fragment is contained in a chemical that is minimally
exposed in the system; its prediction remains questionable. Prediction
of a toxicology endpoint is more often performed on a parent chemical
structure and such experiment that preclude the metabolite, especially
in cases where the metabolite is the principal source of toxicity and
could be misleading. Such an experiment that does not consider
metabolites of parent compounds has implications for the drug
discovery process [54,55].
Read full chapter
View full topic index
About ScienceDirectRemote accessShopping cartContact and
supportTerms and conditionsPrivacy policy
Cookies are used by this site. For more information, visit the cookies
page.
Copyright © 2018 Elsevier B.V. or its licensors or contributors.
ScienceDirect ® is a registered trademark of Elsevier B.V.