Drug design

Drug design, often referred to as rational drug

design or simply rational design, is the inventive
process of finding new medications based on the
knowledge of a biological target.[1] The drug is most
commonly an organic small molecule that activates or
inhibits the function of a biomolecule such as a
protein, which in turn results in a therapeutic benefit to
the patient. In the most basic sense, drug design
involves the design of molecules that are
complementary in shape and charge to the
biomolecular target with which they interact and
therefore will bind to it. Drug design frequently but
not necessarily relies on computer modeling
techniques.[2] This type of modeling is sometimes
referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-
dimensional structure of the biomolecular target is known as structure-based drug design.[2] In addition
to small molecules, biopharmaceuticals including peptides[3][4] and especially therapeutic antibodies are an
increasingly important class of drugs and computational methods for improving the affinity, selectivity, and
stability of these protein-based therapeutics have also been developed.[5]

The phrase "drug design" is to some extent a misnomer. A more accurate term is ligand design (i.e., design
of a molecule that will bind tightly to its target).[6] Although design techniques for prediction of binding
affinity are reasonably successful, there are many other properties, such as bioavailability, metabolic half-
life, side effects, etc., that first must be optimized before a ligand can become a safe and efficacious drug.
These other characteristics are often difficult to predict with rational design techniques. Nevertheless, due to
high attrition rates, especially during clinical phases of drug development, more attention is being focused
early in the drug design process on selecting candidate drugs whose physicochemical properties are
predicted to result in fewer complications during development and hence more likely to lead to an
approved, marketed drug.[7] Furthermore, in vitro experiments complemented with computation methods
are increasingly used in early drug discovery to select compounds with more favorable ADME (absorption,
distribution, metabolism, and excretion) and toxicological profiles.[8]

Drug targets
A biomolecular target (most commonly a protein or a nucleic acid) is a key molecule involved in a
particular metabolic or signaling pathway that is associated with a specific disease condition or pathology or
to the infectivity or survival of a microbial pathogen. Potential drug targets are not necessarily disease
causing but must by definition be disease modifying.[9] In some cases, small molecules will be designed to
enhance or inhibit the target function in the specific disease modifying pathway. Small molecules (for
example receptor agonists, antagonists, inverse agonists, or modulators; enzyme activators or inhibitors; or
ion channel openers or blockers)[10] will be designed that are complementary to the binding site of
target.[11] Small molecules (drugs) can be designed so as not to affect any other important "off-target"
molecules (often referred to as antitargets) since drug interactions with off-target molecules may lead to
undesirable side effects.[12] Due to similarities in binding sites, closely related targets identified through
sequence homology have the highest chance of cross reactivity and hence highest side effect potential.
Most commonly, drugs are organic small molecules produced through chemical synthesis, but biopolymer-
based drugs (also known as biopharmaceuticals) produced through biological processes are becoming
increasingly more common.[13] In addition, mRNA-based gene silencing technologies may have
therapeutic applications.[14]

Rational drug discovery

In contrast to traditional methods of drug discovery (known as forward pharmacology), which rely on trial-
and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to
treatments, rational drug design (also called reverse pharmacology) begins with a hypothesis that
modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be
selected as a drug target, two essential pieces of information are required. The first is evidence that
modulation of the target will be disease modifying. This knowledge may come from, for example, disease
linkage studies that show an association between mutations in the biological target and certain disease
states.[15] The second is that the target is "druggable". This means that it is capable of binding to a small
molecule and that its activity can be modulated by the small molecule.[16]

Once a suitable target has been identified, the target is normally cloned and produced and purified. The
purified protein is then used to establish a screening assay. In addition, the three-dimensional structure of
the target may be determined.

The search for small molecules that bind to the target is begun by screening libraries of potential drug
compounds. This may be done by using the screening assay (a "wet screen"). In addition, if the structure of
the target is available, a virtual screen may be performed of candidate drugs. Ideally the candidate drug
compounds should be "drug-like", that is they should possess properties that are predicted to lead to oral
bioavailability, adequate chemical and metabolic stability, and minimal toxic effects.[17] Several methods
are available to estimate druglikeness such as Lipinski's Rule of Five and a range of scoring methods such
as lipophilic efficiency.[18] Several methods for predicting drug metabolism have also been proposed in the
scientific literature.[19]

Due to the large number of drug properties that must be simultaneously optimized during the design
process, multi-objective optimization techniques are sometimes employed.[20] Finally because of the
limitations in the current methods for prediction of activity, drug design is still very much reliant on
serendipity[21] and bounded rationality.[22]

Computer-aided drug design

The most fundamental goal in drug design is to predict whether a given molecule will bind to a target and if
so how strongly. Molecular mechanics or molecular dynamics is most often used to estimate the strength of
the intermolecular interaction between the small molecule and its biological target. These methods are also
used to predict the conformation of the small molecule and to model conformational changes in the target
that may occur when the small molecule binds to it.[3][4] Semi-empirical, ab initio quantum chemistry
methods, or density functional theory are often used to provide optimized parameters for the molecular
mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential,
polarizability, etc.) of the drug candidate that will influence binding affinity.[23]

Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding
affinity. Also, knowledge-based scoring function may be used to provide binding affinity estimates. These
methods use linear regression, machine learning, neural nets or other statistical techniques to derive
predictive binding affinity equations by fitting experimental affinities to computationally derived interaction
energies between the small molecule and the target.[24][25]

Ideally, the computational method will be able to predict affinity before a compound is synthesized and
hence in theory only one compound needs to be synthesized, saving enormous time and cost. The reality is
that present computational methods are imperfect and provide, at best, only qualitatively accurate estimates
of affinity. In practice it still takes several iterations of design, synthesis, and testing before an optimal drug
is discovered. Computational methods have accelerated discovery by reducing the number of iterations
required and have often provided novel structures.[26][27]

Drug design with the help of computers may be used at any of the following stages of drug discovery:

1. hit identification using virtual screening (structure- or ligand-based design)

2. hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.)
3. lead optimization of other pharmaceutical properties while maintaining affinity

In order to overcome the insufficient

prediction of binding affinity
calculated by recent scoring functions,
the protein-ligand interaction and
compound 3D structure information
are used for analysis. For structure-
based drug design, several post-
screening analyses focusing on
protein-ligand interaction have been
developed for improving enrichment
and effectively mining potential
candidates:

Consensus scoring[28][29]
Selecting candidates by
voting of multiple scoring Flowchart of a Usual Clustering Analysis for Structure-Based Drug
functions Design
May lose the relationship
between protein-ligand
structural information and scoring criterion
Cluster analysis[30][31]
Represent and cluster candidates according to protein-ligand 3D information
Needs meaningful representation of protein-ligand interactions.

Types
There are two major types of drug design. The first is referred to as ligand-based drug design and the
second, structure-based drug design.[2] Both of these strategies can be explored using Cresset's software
Flare.

Ligand-based
Ligand-based drug design (or indirect
drug design) relies on knowledge of
other molecules that bind to the
biological target of interest. These
other molecules may be used to derive
a pharmacophore model that defines
the minimum necessary structural
characteristics a molecule must possess
in order to bind to the target.[32] In
other words, a model of the biological
target may be built based on the
knowledge of what binds to it, and this
model in turn may be used to design
new molecular entities that interact
with the target. Alternatively, a
quantitative structure-activity
relationship (QSAR), in which a Drug discovery cycle highlighting both ligand-based (indirect) and
correlation between calculated structure-based (direct) drug design strategies.
properties of molecules and their
experimentally determined biological
activity, may be derived. These QSAR relationships in turn may be used to predict the activity of new
analogs.[33]

Structure-based

Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure
of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy.[34]
If an experimental structure of a target is not available, it may be possible to create a homology model of the
target based on the experimental structure of a related protein. Using the structure of the biological target,
candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed
using interactive graphics and the intuition of a medicinal chemist. Alternatively various automated
computational procedures may be used to suggest new drug candidates.[35]

Current methods for structure-based drug design can be divided roughly into three main categories.[36] The
first method is identification of new ligands for a given receptor by searching large databases of 3D
structures of small molecules to find those fitting the binding pocket of the receptor using fast approximate
docking programs. This method is known as virtual screening. A second category is de novo design of new
ligands. In this method, ligand molecules are built up within the constraints of the binding pocket by
assembling small pieces in a stepwise manner. These pieces can be either individual atoms or molecular
fragments. The key advantage of such a method is that novel structures, not contained in any database, can
be suggested.[37][38][39] A third method is the optimization of known ligands by evaluating proposed
analogs within the binding cavity.[36]

Binding site identification

Binding site identification is the first step in structure based design.[16][40] If the structure of the target or a
sufficiently similar homolog is determined in the presence of a bound ligand, then the ligand should be
observable in the structure in which case location of the binding site is trivial. However, there may be
unoccupied allosteric binding sites that may be of interest. Furthermore, it may be that only apoprotein
(protein without ligand) structures are available and the reliable identification of unoccupied sites that have
the potential to bind ligands with high affinity is non-trivial. In brief, binding site identification usually relies
on identification of concave surfaces on the protein that can accommodate drug sized molecules that also
possess appropriate "hot spots" (hydrophobic surfaces, hydrogen bonding sites, etc.) that drive ligand
binding.[16][40]

Scoring functions

Structure-based drug design attempts to use the structure of proteins as a basis for designing new ligands by
applying the principles of molecular recognition. Selective high affinity binding to the target is generally
desirable since it leads to more efficacious drugs with fewer side effects. Thus, one of the most important
principles for designing or obtaining potential new ligands is to predict the binding affinity of a certain
ligand to its target (and known antitargets) and use the predicted affinity as a criterion for selection.[41]

One early general-purposed empirical scoring function to describe the binding energy of ligands to
receptors was developed by Böhm.[42][43] This empirical scoring function took the form:

where:

ΔG0 – empirically derived offset that in part corresponds to the overall loss of translational
and rotational entropy of the ligand upon binding.
ΔGhb – contribution from hydrogen bonding
ΔGionic – contribution from ionic interactions
ΔGlip – contribution from lipophilic interactions where |Alipo| is surface area of lipophilic
contact between the ligand and receptor
ΔGrot – entropy penalty due to freezing a rotatable in the ligand bond upon binding

A more general thermodynamic "master" equation is as follows:[44]

where:

desolvation – enthalpic penalty for removing the ligand from solvent

motion – entropic penalty for reducing the degrees of freedom when a ligand binds to its
receptor
configuration – conformational strain energy required to put the ligand in its "active"
conformation
interaction – enthalpic gain for "resolvating" the ligand with its receptor

The basic idea is that the overall binding free energy can be decomposed into independent components that
are known to be important for the binding process. Each component reflects a certain kind of free energy
alteration during the binding process between a ligand and its target receptor. The Master Equation is the
linear combination of these components. According to Gibbs free energy equation, the relation between
dissociation equilibrium constant, Kd , and the components of free energy was built.

Various computational methods are used to estimate each of the components of the master equation. For
example, the change in polar surface area upon ligand binding can be used to estimate the desolvation
energy. The number of rotatable bonds frozen upon ligand binding is proportional to the motion term. The
configurational or strain energy can be estimated using molecular mechanics calculations. Finally the
interaction energy can be estimated using methods such as the change in non polar surface, statistically
derived potentials of mean force, the number of hydrogen bonds formed, etc. In practice, the components of
the master equation are fit to experimental data using multiple linear regression. This can be done with a
diverse training set including many types of ligands and receptors to produce a less accurate but more
general "global" model or a more restricted set of ligands and receptors to produce a more accurate but less
general "local" model.[45]

Examples
A particular example of rational drug design involves the use of three-dimensional information about
biomolecules obtained from such techniques as X-ray crystallography and NMR spectroscopy. Computer-
aided drug design in particular becomes much more tractable when there is a high-resolution structure of a
target protein bound to a potent ligand. This approach to drug discovery is sometimes referred to as
structure-based drug design. The first unequivocal example of the application of structure-based drug
design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide, which was approved
in 1995.[46][47]

Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed
specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive
leukemias (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). Imatinib is
substantially different from previous drugs for cancer, as most agents of chemotherapy simply target rapidly
dividing cells, not differentiating between cancer cells and other tissues.[48]

Additional examples include:

Many of the atypical antipsychotics Nonbenzodiazepines like zolpidem and

Cimetidine, the prototypical H2-receptor zopiclone
antagonist from which the later members of Raltegravir, an HIV integrase inhibitor[49]
the class were developed SSRIs (selective serotonin reuptake
Selective COX-2 inhibitor NSAIDs inhibitors), a class of antidepressants
Enfuvirtide, a peptide HIV entry inhibitor Zanamivir, an antiviral drug

Case studies
5-HT3 antagonists HIV protease inhibitors
Acetylcholine receptor agonists NK1 receptor antagonists
Angiotensin receptor antagonists Non-nucleoside reverse transcriptase
Bcr-Abl tyrosine-kinase inhibitors inhibitors
Cannabinoid receptor antagonists Nucleoside and nucleotide reverse
transcriptase inhibitors
CCR5 receptor antagonists
PDE5 inhibitors
Cyclooxygenase 2 inhibitors
Proton pump inhibitors
Dipeptidyl peptidase-4 inhibitors
Renin inhibitors
 Triptans c-Met inhibitors
TRPV1 antagonists

Criticism
It has been argued that the highly rigid and focused nature of rational drug design suppresses serendipity in
drug discovery.[50]

See also
Bioisostere List of pharmaceutical companies
Bioinformatics Medicinal chemistry
Cheminformatics Molecular design software
Drug development Molecular modification
Drug discovery Retrometabolic drug design

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External links
Drug+Design (https://meshb.nlm.nih.gov/record/ui?name=Drug+Design) at the U.S. National
Library of Medicine Medical Subject Headings (MeSH)

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