calculation of molecular properties, lipinski “rule of five”, prediction...
TRANSCRIPT
CHAPTER 3
Calculation of molecular properties, Lipinski
“Rule of Five”, prediction of bioactivity score
3.Molecular properties, Lipinski “Rule of Five” and Bioactivity score:
This chapter highlights the importance of Lipinski “Rule of Five”,
Calculation of important molecular properties such as logP, polar surface area,
number of hydrogen bond donors, number of hydrogen bond acceptors and
molecular weight, as well as prediction of bioactivity score for the most important
drug targets like GPCR ligands, kinase inhibitors, ion channel modulators and
nuclear receptors.
Experimental and computational approaches to estimate solubility and
permeability in discovery and development settings are described. In the discovery
setting `the rule of 5' predicts that poor absorption or permeation is more likely
when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular
weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater
than 5 (or MlogP>4.15). Computational methodology for the rule-based Moriguchi
Log P (MLogP) calculation is described. Turbidimetric solubility measurement is
described and applied to known drugs. High throughput screening (HTS) leads
tend to have higher MWT and Log P and lower turbidimetric solubility than leads
in the pre-HTS era. In the development setting, solubility calculations focus on
exact value prediction and are difficult because of polymorphism. Recent work on
linear free energy relationships and Log P approaches are critically reviewed.
Useful predictions are possible in closely related analog series when coupled with
experimental thermodynamic solubility measurements.
3.1 Lipinski's rule of five:
Lipinski's rule of five (RO5) is a rule of thumb to evaluate druglikeness
or determine if a chemical compound with a certain pharmacological or biological
activity has properties that would make it a likely orally active drug in humans.
The rule was formulated by Christopher A. Lipinski in 1997, based on the
observation that most medication drugs are relatively small and lipophilic
molecules.The rule describes molecular properties important for a drug's
pharmacokinetics in the human body, including their absorption, distribution,
metabolism, and excretion ("ADME"). However, the rule does not predict if a
compound is pharmacologically active.
The rule is important to keep in mind during drug discovery when a
pharmacologically active lead structure is optimized step-wise to increase the
activity and selectivity of the compound as well as to insure drug-like
physicochemical properties are maintained as described by Lipinski's rule.
Candidate drugs that conform to the RO5 tend to have lower attrition rates during
clinical trials and hence have an increased chance of reaching the market.
3.1.1 Components of the rule
Lipinski's rule states that, in general, an orally active drug has no more
than one violation of the following criteria:
• Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one
or more hydrogen atoms)
• Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
• A molecular mass less than 500 daltons
• An octanol-water partition coefficient log P not greater than 5
Note that all numbers are multiples of five, which is the origin of the rule's name.
3.1.2 Variants
In an attempt to improve the predictions of druglikeness, the rules have spawned
many extensions, for example the following:
• Partition coefficient log P in −0.4 to +5.6 range
• Molar refractivity from 40 to 130
• Molecular weight from 180 to 500
• Number of atoms from 20 to 70 (includes H-bond donors [e.g.;OH's and
NH's] and H-bond acceptors [e.g.; N's and O's])
• Polar surface area no greater than 140 Ǻ2
Also the 500 molecular weight cutoff has been questioned. Polar surface area and
the number of rotatable bonds has been found to better discriminate between
compounds that are orally active and those that are not for a large data set of
compounds. In particular, compounds which meet only the two criteria of:
• 10 or fewer rotatable bonds and
• polar surface area equal to or less than 140 Å2
are predicted to have good oral bioavailability.
3.1.3 Lead-like
During drug discovery, lipophilicity and molecular weight are often
increased in order to improve the affinity and selectivity of the drug candidate.
Hence it is often difficult to maintain drug-likeness (i.e., RO5 compliance) during
hit and lead optimization. Hence it has been proposed that members of screening
libraries from which hits are discovered should be biased toward lower molecular
weight and lipophility so that medicinal chemists will have an easier time in
delivering optimized drug development candidates that are also drug-like. Hence
the rule of five has been extended to the rule of three (RO3) for defining lead-like
compounds.
A rule of three compliant compound is defined as one that has:
• octanol-water partition coefficient log P not greater than 3
• molecular mass less than 300 daltons
• not more than 3 hydrogen bond donors
• not more than 3 hydrogen bond acceptors
• not more than 3 rotatable bonds
This is best explained using the below graphical representation (Fig 3.1)
of chemical space introduced by Lipinski and Hopkins where compounds are
mapped onto coordinates of chemical descriptors of physicochemical or
topological properties. For example, it is known that active site inhibitors for
protease families cluster together in a discrete region of chemical space. The
intersection of this cluster with the descriptor space for drug-like compounds
would contain in this example the protease inhibitors that have the potential to be
developed as oral drugs. Such an overlap would allow the conclusion that the
protease family is druggable. The most challenging part of a protease inhibitor
optimization is changing a peptidic lead compound into an orally bioavailable
peptidomimetic. This step has proven to be relatively straightforward for some
proteases (e.g. thrombin), whereas for others it may be an almost impossible job
due to the amino acid content of the lead and the shallowness of the binding
pocket. The latter case would probably constitute an exception in the generally
druggable protease family (Fig 3.2). Such subtleties create uncertainties about the
reliability of druggability arguments for strategic decision making, especially in
cases of well validated targets with borderline druggability.
A first step towards a more reliable way to assess the druggability of
individual proteins is the identification of binding sites for drug-like molecules.
Kellenberger and co-workers have created an annotated database of ligand binding
sites extracted from several experimental structure databases. Such data can be
used to derive rules or training sets for the computational identification of binding
pockets. Many algorithms are available for this purpose and in general they have
been successfully applied in identifying true ligand binding pockets on the surface
of proteins.
(Fig 3.1) Representation of the relationship between the continuum of chemical space
A graphical representation of the relationship between the continuum of
chemical space (light blue) and the discrete areas occupied by compounds with
specific affinity for certain protein classes. The independent intersection of
compounds with drug-like properties is shown in green. The second step of
quantitatively assessing the druggability of the identified pockets is more
challenging. An obvious approach is to screen a large library of drug-like
compounds (pharmaceutical compound collection or a chemical genetics library
and assess the resulting hits. Unfortunately, this approach has three significant
drawbacks: it is very expensive, applied rather late in the drug discovery process
and it produces a large number of false positives and promiscuous hits which
complicate the analysis.
Fig 3.2 the chemical space occupied by active site serine protease inhibitors.
A close-up of the Fig 3.1 that shows the chemical space occupied by
active site serine protease inhibitors. Since this bubble intersects with the oral
drug-like space, we would come to the conclusion that the serine protease family is
druggable. The situation is, however, more complex. Some serine proteases will be
druggable whereas others are not.
Another method has recently been developed by researchers from
Abbott. Using 2-D heteronuclear-NMR they studied the interactions of 10 000
lead-like or fragment-like compounds with protein surfaces. This approach has the
advantage that it samples a large fraction of chemical space (even though the size
of the library is small) and yields more reliable data than conventional high-
throughput screening. Furthermore, such an NMR based analysis of druggability
could be performed with limited resources and relatively early in the drug
discovery process. Most importantly, an analysis of the NMR data has led to the
development of ‘druggability-indices’ that can be used for the computational
assessment of proteins with known structure. Such quantitative assessments of
druggability would find wide application if it were not for the limited availability
of experimental 3-D structures. Despite the progress that has been made in
structural biology, especially with the structural genomics approaches, only a small
fraction of all proteins have been experimentally characterized. As a consequence,
most structure-based assessments of target druggability still need to be performed
with homology models. Unfortunately the predictive quality of homology models
and therefore their usefulness is rather uncertain since often no closely related
protein with known 3-D structure is available.
3.1.4 Exception to the rule of five:
In the period 1970-2006, a total of 24 unique natural products were
discovered that led to an approved drug. We analyze these successful leads in
terms of drug-like properties, and show that they can be divided into two equal
subsets. The first falls in the 'Lipinski universe' and complies with the Rule of Five.
The second is a 'parallel universe' that violates the rules. Nevertheless, the latter
compounds remain largely compliant in terms of logP and H-bond donors,
highlighting the importance of these two metrics in predicting bioavailability.
Natural products are often cited as an exception to Lipinski's rules. We believe this
is because nature has learned to maintain low hydrophobicity and intermolecular
H-bond donating potential when it needs to make biologically active compounds
with high molecular weight and large numbers of rotatable bonds. In addition,
natural products are more likely than purely synthetic compounds to resemble
biosynthetic intermediates or endogenous metabolites, and hence take advantage of
active transport mechanisms. Interestingly, the natural product leads in the Lipinski
and parallel universe had an identical success rate (50%) in delivering an oral drug.
Compound classes that are substrates for biological transporters:
• Antibiotics
• Fungicides-Protozoacides -antiseptics
• Vitamins
• Cardiac glycosides.
3.1.5 Conclusion on RO5:
The RO5 and its extensions have been useful tools to generate awareness
about the importance of PK parameters for development. In addition, this concept
has led to the realization that there may be whole families of proteins for which it
is either extremely challenging or impossible to design compounds with good oral
bioavailability.
The available evidence suggests that qualitative druggability arguments
are useful strategic tools; however, more accurate, quantitative assessments are
needed, especially for proteins with borderline druggability. Recent developments
suggest that NMR-based screening could deliver such information. In our view,
this is a very attractive approach that can be used in the early stages of drug
discovery and provides a solid basis for computational druggability estimations. It
has been suggested that the inability of the pharmaceutical industry to solve
druggability problems is due to limitations in current medicinal chemistry
approaches. As outlined above, druggability is defined by molecular properties and
therefore it is unlikely that advances in synthesis, profiling or innovative design
will solve these problems. The much-quoted advances in this area (e.g., finding
rinhibitors for protein–protein interactions) rarely address the real problems: PK
and especially oral bioavailability. It is often possible to find inhibitors of proteins
with questionable druggability, but this is only the first step.
The real druggability challenge arrives when these ‘leads’ have to be
turned into orally bio available, pharmaceutically useful drug candidates. It has
never been challenging to make inhibitors of proteins with questionable
druggability, but rather the challenge has been to make orally bio available,
pharmaceutically useful inhibitors that successfully advance through clinical
evelopment. It is likely that oral drugs for the modulation of such proteins will
continue to come from the natural-product pool. In addition, future advances in
drug delivery may offer solutions to address problems of druggability.
3.2 Biological activity
In pharmacology, biological activity or pharmacological activity
describes the beneficial or adverse effects of a drug on living matter. When a drug
is a complex chemical mixture, this activity is exerted by the substance's active
ingredient or pharmacophore but can be modified by the other constituents.
Activity is generally dosage-dependent. Further, it is common to have effects
ranging from beneficial to adverse for one substance when going from low to high
doses. Activity depends critically on fulfillment of the ADME criteria. Whereas a
material is considered bioactive if it has interaction with or effect on any cell tissue
in the human body, pharmacological activity is usually taken to describe beneficial
effects, i.e. the effects of drug candidates as well as a substance's toxicity.
3.2.1 Biological target
A biological target is a biopolymer such as a protein or nucleic acid
whose activity can be modified by an external stimulus. The definition is context-
dependent and can refer to the biological target of a pharmacologically active drug
compound, or the receptor target of a hormone (like insulin). The implication is
that a molecule is "hit" by a signal and its behavior is thereby changed. Biological
targets are most commonly proteins such as enzymes, ion channels, and receptors.
3.2.2 Mechanism
The external stimulus (i.e., chemical substance) physically binds to the
biological target. The interaction between the substance and the target may be:
• Noncovalent
• Reversible covalent - A chemical reaction occurs between the stimulus and
target in which the stimulus becomes chemically bonded to the target, but
the reverse reaction also readily occurs in which the bond can be broken.
• Irreversible covalent - The stimulus is permanently bound to the target
through irreversible chemical bond formation.
Depending on the nature of the stimulus, the following can occur:
• There is no direct change in the biological target, except that the binding of
the substance prevents other endogenous substances such as activating
hormone to bind to the target. Depending on the nature of the target, this
effect is referred as receptor antagonism, enzyme inhibition, or ion channel
blockade.
• A conformational change in the target is induced by the stimulus which
results in a change in target function. This change in function can mimic the
effect of the endogenous substance in which case the effect is referred to as
receptor agonism (or channel or enzyme activation) or be the opposite of the
endogenous substance which in the case of receptors is referred to as inverse
agonism.
3.2.3 Drug targets
The term biological target is frequently used in pharmaceutical research to
describe the native protein in the body whose activity is modified by a drug
resulting in a desirable therapeutic effect. In this context, the biological target is
often referred to as a drug target. The most common drug targets of currently
marketed drugs include:
• Proteins
o G protein-coupled receptors (GPCR) (target of 50% of drugs)
o Enzymes (especially protein kinases, proteases, esterases, and
phosphatases)
o Ion channels
� ligand-gated ion channels
� voltage-gated ion channels
o Nuclear hormone receptors
o Structural proteins such as tubulin
o Membrane transport proteins
• Nucleic acids.
3.2.4 G protein-coupled receptor
G protein coupled receptors (GPCRs) are also known as seven-
transmembrane domain receptors, heptahelical receptors, serpentine receptor, and
G protein-linked receptors (GPLR), constitute a large protein family of receptors
that sense molecules outside the cell and activate inside signal transduction
pathways and, ultimately, cellular responses. They are called transmembrane
receptors because they pass through the cell membrane, and they are called seven-
transmembrane receptors because they pass through the cell membrane seven
times. G protein-coupled receptors are found only in eukaryotes, including yeast,
choanoflagellates and animals. The ligands that bind and activate these receptors
include light-sensitive compounds, odors, pheromones, hormones, and
neurotransmitters, and vary in size from small molecules to peptides to large
proteins.
G protein-coupled receptors are involved in many diseases, and are also
the target of approximately 40% of all modern medicinal drugs. The 2012 Nobel
prize in chemistry was awarded to Brian Kobilka and Robert Lefkowitz for their
work that was "crucial for understanding how G-protein–coupled receptors
function." There are two principal signal transduction pathways involving the G
protein-coupled receptors: the cAMP signal pathway and the phosphatidylinositol
signal pathway. When a ligand binds to the GPCR it causes a conformational
change in the GPCR, which allows it to act as a guanine nucleotide exchange
factor (GEF). The GPCR can then activate an associated G-protein by exchanging
its bound GDP for a GTP. The G-protein's α subunit, together with the bound GTP,
can then dissociate from the β and γ subunits to further affect intracellular
signaling proteins or target functional proteins directly depending on the α subunit
type (Gαsr, Gαi/o, Gαq/11, Gα12/13).
3.2.5 Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by
chemically adding phosphate groups to them (phosphorylation). Phosphorylation
usually results in a functional change of the target protein (substrate) by changing
enzyme activity, cellular location, or association with other proteins. The human
genome contains about 500 protein kinase genes and they constitute about 2% of
all human genes. Protein kinases are also found in bacteria and plants. Up to 30%
of all human proteins may be modified by kinase activity, and kinases are known
to regulate the majority of cellular pathways, especially those involved in signal
transduction.The chemical activity of a kinase involves transferring a phosphate
group from a nucleoside triphosphate (usually ATP) and covalently attaching it to
specific amino acids with a free hydrorxyl group. Most kinases act on both serine
and threonine (serine/threonine kinases), others act on tyrosine (tyrosine kinases),
and a number act on all three (dual-specificity kinases). There are also protein
kinases that phosphorylate other amino acids, including histidine kinases that
phosphorylate histidine residues.
The human protein kinase family is divided into the following groups and
shown in table 3.1:
Tab 3.1:
Protein kinase groups
AGC kinases Containing PKA, PKC and PKG.
CaM kinases The calcium/calmodulin-dependent protein kinases.
CK1 Containing the casein kinase 1 group.
CMGC Containing CDK, MAPK, GSK3 and CLK kinases.
STE Containing the homologs of yeast Sterile 7, Sterile 11, and Sterile 20 kinases.
TK Containing the tyrosine kinases.
TKL Containing the tyrosine-kinase like
group of kinases.
3.2.6 Inhibitors
Deregulated kinase activity is a frequent cause of disease, in particular
cancer, wherein kinases regulate many aspects that control cell growth, movement
and death. Drugs that inhibit specific kinases are being developed to treat several
diseases, and some are currently in clinical use, including Gleevec (imatinib) and
Iressa (gefitinib).
A protein kinase inhibitor is a type of enzyme inhibitor that specifically
blocks the action of one or more protein kinases. Protein kinases are enzymes that
add a phrosphate (PO4) group to a protein or other organic molecule, usually on the
serine, threonine, or tyrosine amino acid. Hence, protein kinase inhibitors can be
subdivided or characterised by the amino acids whose phosphorylation is inhibited:
most kinases act on both serine and threonine, the tyrosine kinases act on tyrosine,
and a number (dual-specificity kinases) act on all three. There are also protein
kinases that phosphorylate other amino acids, including histidine kinases that
phosphorylate histidine residues. Phosphorylation is a necessary step in some
cancers and inflammatory diseases. Inhibiting the protein kinases, and therefore the
phosphorylation, can treat these diseases. Therefore, protein kinase inhibitors are
used as drugs.
Kinase inhibitors such as dasatinib are often used in the treatment of
cancer and inflammation. The novel kinase inhibitor PLX5568 is currently in
clinical trials for treatment of polycystic kidney disease as well as pain. Some of
the kinase inhibitors used in treating cancer are inhibitors of tyrosine kinases. The
effectiveness of kinase inhibitors on various cancers can vary from patient to
patient.
Table 3.2
Drugs, launched or in development that target protein kinases and the receptors that activate them.
Name Target Company Class FDA
approval
Afatinib EGFR/ErbB2 Boehringer
Ingelheim
Small
molecule
Not yet
Axitinib VEGFR1/VEGFR2
/VEGFR3/PDGFR
B/c-KIT
Pfizer Small
molecule
2012 Renal
cell
carcinoma
Bevacizu
mab
VEGF Genentech Monoclona
l antibody
2004
Colorectal
Bosutinib BcrAbl /SRC Pfizer Small
molecule
2012
Chronic
myelogenou
s leukemia
Cetuxima
b
ErbB1 Imclone/BMS Monoclona
l antibody
2006 Mar
(SCCHN)
Crizotinib ALK/Met Pfizer Small
molecule
2011 Aug
(NSCLC
with Alk
mutation)
Dasatinib multiple targets BMS Small
molecule
2006
Erlotinib ErbB1 Genentech/Ro
che
Small
molecule
2005 Nov?
Fostamati
nib
Syk Rigel
Pharmaceutic
als/AstraZene
ca
Small
molecule
Not yet [1]
Gefitinib EGFR AstraZeneca Small
molecule
2003
Imatinib Bcr-Abl Novartis Small
molecule
2001
(CML),
2002 (GIST)
[4]
Lapatinib ErbB1/ErbB2 GSK Small
molecule
2007
(HER2+
Breast)
Lenvatini
b
VEGFR2/VEGFR2 Eisai Co. Small
molecule
Not yet
Mubritini
b
? Takeda Small
molecule
Not yet,
possibly
abandoned
Nilotinib Bcr-Abl Novartis Small
molecule
2007
Panitumu
mab
EGFR Amgen Monoclona
l antibody
2006
Pazopanib VEGFR2/PDGFR/
c-kit
GlaxoSmithK
line
Small
molecule
2009 (RCC)
Pegaptani
b
VEGF OSI/Pfizer RNA
Aptamer
2004
(AMD)
Ranibizu
mab
VEGF Genentech Monoclona
l antibody
2006
(AMD)
Ruxolitini
b
JAK Incyte Small
molecule
2011
(Myelofibro
sis)
Sorafenib multiple targets Onyx/Bayer Small
molecule
2005 Dec
(kidney)
Sunitinib multiple targets SUGEN/Pfize
r
Small
molecule
2006 Jan
(RCC &
GIST)
Trastuzu
mab
Erb2 Genentech/Ro
che
Monoclona
l antibody
1998
(HER2+
breast
cancer)
Vandetani
b
RET/VEGFR/EGF
R
AstraZeneca Small
molecule
No,
submission
withdrawn
Oct09 [2]
Vemurafe
nib
BRAF Roche Small
molecule
2011 Aug
Melanoma
3.2.7 Ion channel modulators
Ion channels allow the movement of charged particles, known as ions,
across cell membranes. Ion channels function in a variety of biological pathways
including the firing of neurons and muscle cells and the activation of immune cells.
Ion channels are used to restore the balance of ions across a membrane.
When open, ion channels allow charged molecules to move from an area of high
concentration to low concentration without using energy. Ion channels serve as a
counterbalance to active transport, a process whereby a cell uses energy to actively
pump ions and other charged molecules across a membrane in order to establish
ion gradients or alter the pH of an organelle to activate enzymes. There are two
major types of ion channels:
• Voltage-gated ion channels
• Ligand-gated ion channels
When ions are present in a higher concentration on one side of a
membrane than the other, a difference in voltage occurs across that membrane,
creating a membrane potential. Voltage-gated ion channels open in response to a
change in membrane potential, allowing the ions to move from the side of the
membrane with the higher ion concentration to the side with the lower ion
concentration.
Ligand-gated ion channels rely on the binding of a small molecule to
the channel. The small molecule binding causes a change in the channel protein,
opening the pore for the ions to travel through. As with voltage-gated ion channels,
when ligand-gated ion channels open ions move from the side of the membrane
with the higher ion concentration to the side with the lower ion concentration.
When targeted by therapeutics, ion channels are either inhibited,
preventing the flow of ions, or held constitutively open by the action of agonists,
preventing the accumulation of ions on one side of the membrane. The desired
activity of the ion channel modulator depends on the disease being targeted.
Table 3.3:
There are several ion channel modulators currently in use. Examples are included in the table below.
Channel
Type Target Name Development Status
Voltage-
gated
Ca2+ channel Multiple FDA approved anti-hypertensives
Na+ channel
Multiple FDA approved products including
local anaesthetics and anticonvulsants
K+ channel Multiple sulfonylureas approved for diabetes
Ligand-
gated
Glutamate-
gated chloride
channel
Ivermectin, FDA approved for onchocerciasis
and in use for the treatment of lymphatic
filariasis
Acetylcholine-
gated chloride
Levamisole, pyrantal, and tribendamadine
(China only), for treatment of helminth
channels infections
Multiple FDA approved products for the
treatment of tobacco dependence
Ion Channel Modulators as Non-Neglected Tropical Disease
3.2.8 Therapeutics
Ion channel inhibitors are used to treat a wide range of conditions including:
• Hypertension
• Pain
• Convulsions
• Diabetes
• Tobacco dependence
The most well-known and widely-used ion channel inhibitors are the
calcium channel inhibitors used to treat high blood pressure. The movement of
calcium across cell membranes causes muscle contractions. While this is a normal
biological process, contraction of the muscles of the circulatory system can
exacerbate the condition of patients with high blood pressure or hypertension.
Calcium channel blockers are used in patients with hypertension to reduce
contraction of the smooth muscles of the arteries, allowing the arteries to dilate to
reduce blood pressure.
Ion Channel Modulators as Neglected Tropical Disease Therapeutics
Ion channel inhibitors are used to treat parasitic worm infections including:
• Onchocerciasis
• Lymphatic filariasis
• Ascariasis
• Hookworm
• Schistosomiasis
Ivermectin is a glutamate-gated chloride channel inhibitor that is widely used in
mass drug administration programs in the developing world to treat infections with
parasitic worms that cause onchocerciasis and lymphatic filariasis. Ivermectin is
also used widely in veterinary medicine for the treatment of worm infections. The
drug is believed to work in these organism by inhibiting glutamate-gated chloride
channels, which are only found in invertebrates, allowing these drugs to selectively
target parasitic worms over their human hosts. Disruption of the flow of chloride
causes paralysis and starvation of the worm leading to death.
Levamisole and pyrantal pamoate can be used to treat the soil transmitted
helminths ascariasis and hookworm, but are not widely used. Tribendamadine is
used to treat ascariasis in China but has not been extensively evaluated or used
outside of China. All three of these products are agonists of acetylcholine-gated
chloride channels. These drugs force the chloride channels to remain open rather
inhibiting them; the resulting imbalance of chloride ions results in death of the
worms.
Praziquantel is the only on market drug for the treatment of
schistosomiasis. Although the mechanism of action of praziquantel is not entirely
clear, it is believed that the drug inhibits calcium channels on the parasite. More
research is needed to understand if inhibition of calcium channels is the primary
mechanism of action of praziquantel or part of a multi-target mechanism.
Modulation of ion channel function has been a successful area for drug
development, with ion channel modulating drugs being used in the therapeutic
treatment of epilepsy, hypertension, diabetes and chronic pain. Most of the ion
channel-modulating drugs that are currently on the market were developed without
extensive knowledge of the molecular structure of ion channels, or an
understanding of the full complexity of ion channel subtypes or knowledge of how
ion channel expression is regulated during pathology. As new information on the
roles that different ion channel subtypes play in pathophysiological processes
becomes available, drugs will be designed to target specific ion channel subtypes
via mechanisms that involve either direct channel block or modulation of ion
channel functional expression.
3.2.9 Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins
found within cells that are responsible for sensing steroid and thyroid hormones
and certain other molecules. In response, these receptors work with other proteins
to regulate the expression of specific genes, thereby controlling the development,
homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA and regulate
the expression of adjacent genes, hence these receptors are classified as
transcription factors. The regulation of gene expression by nuclear receptors
generally only happens when a ligand — a molecule that affects the receptor's
behavior — is present. More specifically, ligand binding to a nuclear receptor
results in a conformational change in the receptor, which, in turn, activates the
receptor, resulting in up-regulation or down-regulation of gene expression.
A unique property of nuclear receptors that differentiates them from other
classes of receptors is their ability to directly interact with and control the
expression of genomic DNA. As a consequence, nuclear receptors play key roles in
both embryonic development and adult homeostasis