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Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new
medications A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and re ...
based on the knowledge of a
biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
. The drug is most commonly an
organic Organic may refer to: * Organic, of or relating to an organism, a living entity * Organic, of or relating to an anatomical organ Chemistry * Organic matter, matter that has come from a once-living organism, is capable of decay or is the product ...
small molecule that activates or inhibits the function of a
biomolecule A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or developmental biology, development. Biom ...
such as a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, which in turn results in a therapeutic benefit to the
patient A patient is any recipient of health care services that are performed by healthcare professionals. The patient is most often ill or injured and in need of treatment by a physician, nurse, optometrist, dentist, veterinarian, or other heal ...
. In the most basic sense, drug design involves the design of molecules that are complementary in
shape A shape or figure is a graphical representation of an object or its external boundary, outline, or external surface, as opposed to other properties such as color, texture, or material type. A plane shape or plane figure is constrained to lie ...
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 Computer simulation is the process of mathematical modelling, performed on a computer, which is designed to predict the behaviour of, or the outcome of, a real-world or physical system. The reliability of some mathematical models can be dete ...
techniques. 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. In addition to small molecules,
biopharmaceutical A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
s including
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...
s and especially
therapeutic antibodies Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those ...
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. The phrase "drug design" is to some extent a
misnomer A misnomer is a name that is incorrectly or unsuitably applied. Misnomers often arise because something was named long before its correct nature was known, or because an earlier form of something has been replaced by a later form to which the name ...
. A more accurate term is
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...
design (i.e., design of a molecule that will bind tightly to its target). Although design techniques for prediction of binding affinity are reasonably successful, there are many other properties, such as
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
, metabolic half-life,
side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequenc ...
, 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 Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...
, 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. Furthermore,
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
experiments complemented with computation methods are increasingly used in early
drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or b ...
to select compounds with more favorable
ADME ADME is an abbreviation in pharmacokinetics and pharmacology for "absorption, distribution, metabolism, and excretion", and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug level ...
(absorption, distribution, metabolism, and excretion) and toxicological profiles.


Drug targets

A biomolecular target (most commonly a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
or a
nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main ...
) is a key molecule involved in a particular
metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
or
signaling In signal processing, a signal is a function that conveys information about a phenomenon. Any quantity that can vary over space or time can be used as a signal to share messages between observers. The '' IEEE Transactions on Signal Processing' ...
pathway that is associated with a specific disease condition or
pathology Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
or to the
infectivity In epidemiology, infectivity is the ability of a pathogen to establish an infection. More specifically, infectivity is a pathogen's capacity for horizontal transmission — that is, how frequently it spreads among hosts that are not in a parent ...
or survival of a
microbial A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a g ...
. Potential drug targets are not necessarily disease causing but must by definition be disease modifying. 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
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
s, antagonists,
inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse ago ...
s, or modulators; enzyme activators or inhibitors; or ion channel openers or blockers) will be designed that are complementary to the
binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
of target. 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 In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequenc ...
. Due to similarities in binding sites, closely related targets identified through
sequence homology Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a ...
have the highest chance of cross reactivity and hence highest side effect potential. Most commonly, drugs are
organic Organic may refer to: * Organic, of or relating to an organism, a living entity * Organic, of or relating to an anatomical organ Chemistry * Organic matter, matter that has come from a once-living organism, is capable of decay or is the product ...
small molecules produced through chemical synthesis, but biopolymer-based drugs (also known as
biopharmaceutical A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
s) produced through biological processes are becoming increasingly more common. In addition,
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
-based
gene silencing Gene silencing is the regulation of gene expression in a cell to prevent the expression of a certain gene. Gene silencing can occur during either transcription or translation and is often used in research. In particular, methods used to silence ge ...
technologies may have therapeutic applications.


Rational drug discovery

In contrast to traditional methods of
drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or b ...
(known as forward pharmacology), which rely on
trial-and-error Trial and error is a fundamental method of problem-solving characterized by repeated, varied attempts which are continued until success, or until the practicer stops trying. According to W.H. Thorpe, the term was devised by C. Lloyd Morgan (18 ...
testing of chemical substances on cultured cells or
animal Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage ...
s, 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. 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. Once a suitable target has been identified, the target is normally
cloned Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, ...
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. Several methods are available to estimate druglikeness such as Lipinski's Rule of Five and a range of scoring methods such as lipophilic efficiency. Several methods for predicting drug metabolism have also been proposed in the scientific literature. Due to the large number of drug properties that must be simultaneously optimized during the design process,
multi-objective optimization Multi-objective optimization (also known as multi-objective programming, vector optimization, multicriteria optimization, multiattribute optimization or Pareto optimization) is an area of multiple criteria decision making that is concerned with ...
techniques are sometimes employed. Finally because of the limitations in the current methods for prediction of activity, drug design is still very much reliant on
serendipity Serendipity is an unplanned fortunate discovery. Serendipity is a common occurrence throughout the history of product invention and scientific discovery. Etymology The first noted use of "serendipity" was by Horace Walpole on 28 January 1754. ...
and
bounded rationality Bounded rationality is the idea that rationality is limited when individuals make decisions, and under these limitations, rational individuals will select a decision that is satisfactory rather than optimal. Limitations include the difficulty o ...
.


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 Molecular dynamics (MD) is a computer simulation method for analyzing the physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamic "evolution" of th ...
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.
Semi-empirical Empirical evidence for a proposition is evidence, i.e. what supports or counters this proposition, that is constituted by or accessible to sense experience or experimental procedure. Empirical evidence is of central importance to the sciences and ...
,
ab initio quantum chemistry methods ''Ab initio'' quantum chemistry methods are computational chemistry methods based on quantum chemistry. The term was first used in quantum chemistry by Robert Parr and coworkers, including David Craig in a semiempirical study on the excite ...
, or
density functional theory Density-functional theory (DFT) is a computational quantum mechanical modelling method used in physics, chemistry and materials science to investigate the electronic structure (or nuclear structure) (principally the ground state) of many-body ...
are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential,
polarizability Polarizability usually refers to the tendency of matter, when subjected to an electric field, to acquire an electric dipole moment in proportion to that applied field. It is a property of all matter, considering that matter is made up of elementar ...
, etc.) of the drug candidate that will influence binding affinity. 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 In statistics, linear regression is a linear approach for modelling the relationship between a scalar response and one or more explanatory variables (also known as dependent and independent variables). The case of one explanatory variable is cal ...
,
machine learning Machine learning (ML) is a field of inquiry devoted to understanding and building methods that 'learn', that is, methods that leverage data to improve performance on some set of tasks. It is seen as a part of artificial intelligence. Machine ...
,
neural net Artificial neural networks (ANNs), usually simply called neural networks (NNs) or neural nets, are computing systems inspired by the biological neural networks that constitute animal brains. An ANN is based on a collection of connected units ...
s 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. 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. Drug design with the help of computers may be used at any of the following stages of drug discovery: # hit identification using
virtual screening Virtual screening (VS) is a computational technique used in drug discovery to search libraries of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or enzyme. Virt ...
(structure- or ligand-based design) # hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.) # 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 ** Selecting candidates by voting of multiple scoring functions ** May lose the relationship between protein-ligand structural information and scoring criterion * Cluster analysis ** 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 In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...
-based drug design and the second, structure-based drug design.


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. 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 Quantitative may refer to: * Quantitative research, scientific investigation of quantitative properties * Quantitative analysis (disambiguation) * Quantitative verse, a metrical system in poetry * Statistics, also known as quantitative analysis ...
(QSAR), in which a correlation between calculated properties of molecules and their experimentally determined
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 ...
, may be derived. These QSAR relationships in turn may be used to predict the activity of new analogs.


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 X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
or
NMR spectroscopy Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fi ...
. 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 Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developme ...
. Alternatively various automated computational procedures may be used to suggest new drug candidates. Current methods for structure-based drug design can be divided roughly into three main categories. 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 Virtual screening (VS) is a computational technique used in drug discovery to search libraries of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or enzyme. Virt ...
. 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. A third method is the optimization of known ligands by evaluating proposed analogs within the binding cavity.


Binding site identification

Binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
identification is the first step in structure based design. 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 Concave or concavity may refer to: Science and technology * Concave lens * Concave mirror Mathematics * Concave function, the negative of a convex function * Concave polygon, a polygon which is not convex * Concave set In geometry, a subset o ...
surfaces on the protein that can accommodate drug sized molecules that also possess appropriate "hot spots" (
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...
surfaces,
hydrogen bonding In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
sites, etc.) that drive ligand binding.


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 The term molecular recognition refers to the specific interaction between two or more molecules through noncovalent bonding such as hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, π-π interactions, halogen ...
. Selective high affinity binding to the target is generally desirable since it leads to more
efficacious Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...
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. One early general-purposed empirical scoring function to describe the binding energy of ligands to receptors was developed by Böhm. This empirical scoring function took the form: \Delta G_ = \Delta G_ + \Delta G_ \Sigma_ + \Delta G_ \Sigma_ + \Delta G_ \left\vert A \right\vert + \Delta G_ \mathit 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: \begin\Delta G_ = -RT \ln K_\\ .3ex K_ = \dfrac\\ .3ex \Delta G_ = \Delta G_ + \Delta G_ + \Delta G_ + \Delta G_\end where: * desolvation –
enthalpic Enthalpy , a property of a thermodynamic system, is the sum of the system's internal energy and the product of its pressure and volume. It is a state function used in many measurements in chemical, biological, and physical systems at a constant p ...
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.


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 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. The drug is most commonly an organic small molecule that activ ...
leading to an approved drug is the carbonic anhydrase inhibitor
dorzolamide Dorzolamide, sold under the brand name Trusopt among others, is a medication used to treat high pressure inside the eye, including in cases of glaucoma. It is used as an eye drop. Effects begin within three hours and last for at least eight hour ...
, which was approved in 1995. Another important case study in rational drug design is
imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...
, a
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
inhibitor designed specifically for the ''bcr-abl'' fusion protein that is characteristic for
Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...
-positive
leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
s (
chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumul ...
and occasionally
acute lymphocytic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...
). Imatinib is substantially different from previous drugs for
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, as most agents of
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
simply target rapidly dividing cells, not differentiating between cancer cells and other tissues. Additional examples include: * Many of the
atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
s *
Cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 r ...
, the prototypical H2-receptor antagonist from which the later members of the class were developed * Selective COX-2 inhibitor
NSAID Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
s *
Enfuvirtide Enfuvirtide ( INN) is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon (Roche). Structural formula Enfuvirtide i ...
, a peptide HIV entry inhibitor *
Nonbenzodiazepines Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
like zolpidem and
zopiclone Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases th ...
*
Raltegravir Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential ex ...
, an
HIV integrase Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...
inhibitor *
SSRIs Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellu ...
(selective serotonin reuptake inhibitors), a class of
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common Side effect, side-effects of antidepressants include Xerostomia, dry mouth, weig ...
s * Zanamivir, an
antiviral drug Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...


Case studies

*
5-HT3 antagonists The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With th ...
* Acetylcholine receptor agonists * Angiotensin receptor antagonists * Bcr-Abl tyrosine-kinase inhibitors * Cannabinoid receptor antagonists * CCR5 receptor antagonists * Cyclooxygenase 2 inhibitors *
Dipeptidyl peptidase-4 inhibitors Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2. The first agent of the class – sit ...
* HIV protease inhibitors * NK1 receptor antagonists * Non-nucleoside reverse transcriptase inhibitors * Nucleoside and nucleotide reverse transcriptase inhibitors *
PDE5 inhibitors A phosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplyi ...
*
Proton pump inhibitors Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...
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Renin inhibitors Renin inhibitors are pharmaceutical drugs inhibiting the activity of renin that is responsible for hydrolyzing angiotensinogen to angiotensin I, which in turn reduces the formation of angiotensin II that facilitates blood pressure. Renin inhibi ...
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Triptans Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual headaches, ...
* TRPV1 antagonists * c-Met inhibitors


Criticism

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


See also

* Bioisostere *
Bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...
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Cheminformatics Cheminformatics (also known as chemoinformatics) refers to use of physical chemistry theory with computer and information science techniques—so called "''in silico''" techniques—in application to a range of descriptive and prescriptive problem ...
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Drug development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...
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Drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or b ...
* List of pharmaceutical companies *
Medicinal chemistry Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developme ...
* Molecular design software * Molecular modification * Retrometabolic drug design


References


External links

* {{Medicinal chemistry Design of experiments Drug discovery Medicinal chemistry