This action might not be possible to undo. Are you sure you want to continue?
A drug is a substance which may have medicinal, intoxicating, performance enhancing or other effects when taken or put into a human body or the body of another animal and is not considered a food or exclusively a food. What is considered a drug rather than a food varies between cultures, and distinctions between drugs and foods and between kinds of drug are enshrined in laws which vary between jurisdictions and aim to restrict or prevent drug use. Even within a jurisdiction, however, the status of a substance may be uncertain or contested with respect to both whether it is a drug and how it should be classified if at all. There is no single, precise definition, as there are different meanings in drug control law, government regulations,medicine, and colloquial usage. In pharmacology, a drug is "a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being." Drugs may be prescribed for a limited duration, or on a regular basis forchronic disorders. Recreational drugs are chemical substances that affect the central nervous system, such as opioids or hallucinogens. They may be used for perceived beneficial effects on perception, consciousness, personality, and behavior. Some drugs can causeaddiction and/or habituation. Drugs are usually distinguished from endogenous biochemicals by being introduced from outside the organism. For example, insulin is a hormone that is synthesized in the body; it is called a hormone when it is synthesized by the pancreas inside the body, but if it is introduced into the body from outside, it is called a drug. Many natural substances, such as beers,wines, and psychoactive mushrooms, blur the line between food and recreational drugs, as when ingested they affect the functioning of both mind and body and some substances normally considered drugs such as DMT (Dimethyltryptamine) are actually produced by the human body in trace amounts.
A medication or medicine is a drug taken to cure and/or ameliorate any symptoms of an illness or medical condition, or may be used as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. Dispensing of medication is often regulated by governments into three categories—over-thecounter (OTC) medications, which are available in pharmacies and supermarkets without special restrictions, behind-the-counter (BTC), which are dispensed by apharmacist without needing a doctor's prescription, and prescription only medicines (POM), which must be prescribed by a licensedmedical professional, usually a physician
Spiritual and religious use
The spiritual and religious use of drugs has been occurring since the dawn of our species. Drugs that are considered to have spiritual or religious use are called entheogens. Some religions are based completely on the use of certain drugs. Entheogens are mostly hallucinogens, being either psychedelics or deliriants, but some are also stimulantsand sedatives.
Nootropics, also commonly referred to as "smart drugs", are drugs that are claimed to improve human cognitive abilities. Nootropics are used to improve memory, concentration, thought, mood, learning, and many other things. Some nootropics are now beginning to be used to treat certain diseases such as attention-deficit hyperactivity disorder, Parkinson's disease, and Alzheimer's disease. They are also commonly used to regain brain function lost during aging. Similarly, drugs such as steroids improve human physical capabilities and are sometimes used (legally or not) for this purpose, often by professional athletes.
Recreational drug use
Types of drugs include: • Glues • Paint thinner • Gasoline • Laughing gas • Aerosol sprays . as a liquid or solid. Many other recreational drugs on the other hand are legal. Unfortunately. betel nut. In order to prevent extreme negative side effects of these drugs and the impact they have on life. for the experience. tobacco. • Topically. lung and kidney problems. Because of the legal status of many drugs. or snorted into the nose. Types of drugs include: • Cocaine • Methamphetamines • Amphetamines • Ritalin • Cylert Inhalants Inhalants are sniffed or huffed and give the user immediate results. or to enhance an already positive experience. Constant use of such drugs can have very negative effects on the user. A drug administered in this manner may be given to act locally or systemically. • Rectally as a suppository. and in other localised areas of the world drugs such as Khat are common. Other effects include liver. the user is typically left with feelings of sickness and a loss of energy. and caffeine products in the west. that is absorbed through the intestines. and at the most have an age restriction on using and/or purchasing them. diffusing into the blood through tissues under the tongue. recreational drug use is controversial. When inhalants are taken. Treatment for drug abuse is often sought to aid in recovery. as an aerosol or dry powder. and in serious cases death can occur. both medicinal and recreational. suspension or emulsion either: intramuscular. intraperitoneal. • Vaginally as a suppository. Stimulants have the opposite effect of depressants. widely culturally accepted.Recreational drugs use is the use of psychoactive substances to have fun. These include alcohol. Administering drugs Drugs. intraosseous. intravenous. • Orally. causing a rapid heart beat. Stimulants These drugs speed up the body’s nervous system and create a feeling of energy. • Insufflation. National laws prohibit the use of many different recreational drugs and medicinal drugs that have the potential for recreational use are heavily regulated. Some are legal and others are not. (This includes smoking a substance) • Injected as a solution. • Sublingually. primarily to treat vaginal infections. They are also called “uppers” because of their ability to make you feel very awake. (breathed into the lungs). and can be taken numerous ways. Drug abuse and misuse can cause numerous health problems. with many governments not recognising spiritual or other perceived uses for drugs and classing them under illegal recreational use. 2. Many drugs can be administered in a variety of ways rather than just one. When the effects of a stimulant wear off. Drug Categories Drugs come in various forms. difficulty walking and confusion. drug treatment centers are often recommended. • Bolus • Inhaled. usually as a cream or ointment. these immediate results can also result in sudden mental damage. the body becomes deprived of oxygen. that is absorbed by the rectum or colon. can be administered in a number of ways. affected sense of smell.
cause confusion and memory problems. and often bring about hostility. switching emotions is frequent. feelings of euphoria. Hallucinogens affect the body’s self-control. such as speech and movement. stroke and change in voice. Hostility is also a frequent side effect of anabolic steroids.Cannabinoids These drugs result in feelings of euphoria. acetaminophen Anabolic Steroids Steroids are taken to improve physical performance as well as to enlarge muscles and increase strength. a higher heart rate. although drowsiness is often a side effect. nausea. anxiety. respiratory complications and relieve pain. higher blood pressure and changes in the body’s hormones. These drugs can be used as aids in surgery. Types of drugs include: • LSD (lysergic acid diethylamide) • Mescaline • Psilocybin • Cannabis • Magic Mushrooms Prescription Drugs Prescription drugs can be very helpful drugs when used properly and when under the guidance of a qualified physician. Other negative side effects of these drugs include heart failure. drug treatment is suggested. Types of drugs include: • Hashish • Marijuana Depressants Depressants slow down activity in the central nervous system of your body. heart attack. increased heart rate. oily hair and skin. The “relaxation” felt from these drugs is not a healthy feeling for the body to experience. These drugs change the mind and cause the appearance of things that are not really there. Types of drugs include: • Codeine • Fentanyl and fentanyl analogs • Heroin • Morphine • Opium • Oxycodone HCL • Hydrocodone bitartrate. to treat medical conditions and while . These drugs are also called “downers” because they slow the body down and seem to give feelings of relaxation. acne. Types of drugs include: • Anadrol • Oxandrin • Durabolin • Stanozol • Dianabol Hallucinogens When taking hallucinogens. Depressants are available as prescription drugs to relieve stress and anger. cysts. confusion. Types of drugs: • Barbiturates • Benzodiazepines • Flunitrazepam • GHB (Gamma-hydroxybutyrate) • Methaqualone • Alcohol • Tranquillisers Opioids & Morphine Derivatives Opioids and morphine derivatives can cause drowsiness. to stop abuse of this drug. Negative effects of steroids include baldness. as well as staggering and poor reaction time.
which in turn results in atherapeutic benefit to the patient. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein. Types of drugs include: • Opiods: Codeine. sometimes referred to as rational drug design or more simply rational design. In the most basic sense. Morphine • Central nervous system depressants: barbiturates. a model of the biological target may be built based on the knowledge of what binds to it. benzodiazepines • Stimulants: dextroamphetamine. and this model in turn may be used to design new molecular entities that interact with the target.1 Ligand-based Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. This type of modeling is often referred to as computer-aided drug design.controlling various symptoms.In other words. The first is referred to as ligand-based drug design and the second. 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. Finally. Types Flow charts of two strategies of structure-based drug design There are two major types of drug design. Alternatively. in which a correlation between calculated properties of molecules and their . a quantitative structure-activity relationship (QSAR). drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. 3. drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known asstructure-based drug design. Drug design Drug design. methylphenidate 3. Oxycodone. Misuse and abuse of prescription drugs however can be very dangerous. structure-based drug design. is the inventive process of finding new medications based on the knowledge of abiological target. Drug design frequently but not necessarily relies on computer modeling techniques.
3. In this case. Polar atom: Oxygen and nitrogen atoms that are neither H-bond donor nor H-bond acceptor. Another category of structure-based drug design methods is about “building” ligands. In parallel. The key advantage of database searching is that it saves synthetic effort to obtain new lead compounds. not contained in any database. H-bond acceptor: Oxygen and sp2 or sp hybridized nitrogen atoms with lone electron pair(s). Both ligand and protein atoms need to be classified and their atomic properties should be defined. This method is usually referred as ligand-based drug design. This has encouraged the rapid development of the structure-based drug design. H-bond donor: Oxygen and nitrogen atoms bonded to hydrogen atom(s). basically. derives key interaction sites within the binding pocket. Alternatively various automated computational procedures may be used to suggest new drug candidates. halogen. can be suggested. candidate drugs that are predicted to bind with high affinity andselectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist.experimentally determined biological activity. may be derived. information about the structural dynamics and electronic properties about ligands has also increased. Using the structure of the biological target. It analyzes the protein to find the binding pocket. . which is usually referred as database searching. phosphorus. The key advantage of such a method is that novel structures. Current methods for structure-based drug design can be divided roughly into two categories. the amount of information concerning 3D structures of biomolecular targets has increased dramatically. If an experimental structure of a target is not available. sulfur. The basic inputs for this step are the 3D structure of the protein and a predocked ligand in PDB format. Hence we are clear what kind of chemical fragments can be put into their corresponding spots in the ligand binding region of the receptor. metal. it may be possible to create a homology model of the target based on the experimental structure of a related protein. These pieces can be either individual atoms or molecular fragments. a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. and then prepares the necessary data for Ligand fragment link. into four atomic types: • • • • hydrophobic atom: All carbons in hydrocarbon chains or in aromatic groups. As experimental methods such as X-ray crystallography and NMR develop. ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner. which is usually referred as receptor-based drug design. The first category is about “finding” ligands for a given receptor. as well as their atomic properties. Active site identification Active site identification is the first step in this program. These QSAR relationships in turn may be used to predict the activity of new analogs. The space inside the ligand binding region would be studied with virtual probe atoms of the four types above so the chemical environment of all spots in the ligand binding region can be known.2 Structure-based Structure-based drug design (or direct drug design) relies on knowledge of thethree dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy. In this case. and carbon atoms bonded to hetero-atom(s).
Ligand fragment link Flow chart for structure-based drug design When we want to plant “seeds” into different regions defined by the previous section. The term “fragment” is used here to describe the . we need a fragments database to choose fragments from.
hit-to-lead optimization of affinity and selectivity (structure-based design. First. 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. They are described as “Grow” and “Link”. The reality however is that present computational methods are imperfect and provide at best only qualitatively accurate estimates of affinity. etc. Therefore in practice it still takes several iterations of design. one may think using other possible strategies to let the program works more efficiently. Although the diversity of organic structures is infinite. computational methods have accelerated discovery by reducing the number of iterations required and in addition have often provided more novel small molecule structures. On the other hand. Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. the number of basic fragments is rather limited. 3. When a ligand is inserted into the pocket site of a receptor. and then connect those seeds into a continuous ligand in a manner that make the rest part of the ligand having the lowest energy. The rationale of this algorithm lies in the fact that organic structures can be decomposed into basic chemical fragments. the seed. i. the possibility for the fragment combinations is huge. it is useful to identify potential problems. enhance. polarizability. These methods use linear regression. These two strategies above are well used in most structure-based drug design programs. The two strategies are always combined in order to make the construction result more reliable. Drug design with the help of computers may be used at any of the following stages of drug discovery: 1. machine learning.) of the drug candidate that will influence binding affinity. is put into the binding pocket. etc. it reduces the possibility of the combination of fragments. the scoring function calculation would be done for every step of conformation change of the fragments derived from every type of possible fragments combination. knowledge-based scoring function may be used to provide binding affinity estimates. Since this requires a large amount of computation. or study drugs and related biologically active molecules. At the same time. Therefore it allows us to put several seeds at the same time into the regions that have significant interactions with the seeds and adjust their favorite conformation first. Molecular mechanics or molecular dynamics are most often used to predict the conformation of thesmall molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. Ideally the computational method should be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized. The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly.building blocks used in the construction process. which reduces the number of possible ligands that can be derived from the program. This strategy reduces calculation burden for the fragment construction efficiently. conformation favor for these groups on the ligand that can bind tightly with receptor should be taken priority.) 3. synthesis. QSAR. in order to find the lowest binding energy on the Potential energy surface (PES) between planted fragments and receptor pocket.3 Computer-aided drug design Computer-aided drug design uses computational chemistry to discover. On the other hand. and other fragments can be added one by one. Also. and testing before an optimal molecule is discovered.e. Before the first fragment. hit identification using virtual screening (structure.or ligand-based design) 2. Semiempirical. lead optimization optimization of other pharmaceutical properties while maintaining affinity . The conformations of the pre-placed seeds ensuring the binding affinity decide the manner that ligand would be grown. A small perturbation of the previous fragment conformation would cause great difference in the following construction process. 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. ab initio quantum chemistry methods.
tetracyclines etc. gentamicin. For structure-based drug design. morphine->nalorphine Receptor Based drug design – Receptor is the target (usually a protein) .In order to overcome the insufficient prediction of binding affinity calculated by recent scoring functions. 4. neomycin. the protein-ligand interaction and compound 3D structure information are used to analysis. Chemical Modification of Known Drugs – Drug improvement by chemical modification – Pencillin G -> Methicillin. Important Points in Drug Design based on Bioinformatics Tools History of Drug/Vaccine development Plants or Natural Product • Plant and Natural products were source for medical substance • Example: foxglove used to treat congestive heart failure • Foxglove contain digitalis and cardiotonic glycoside • Identification of active component Accidental Observations • Penicillin is one good example • Alexander Fleming observed the effect of mold • Mold(Penicillium) produce substance penicillin • Discovery of penicillin lead to large scale screening • Soil micoorganism were grown and tested • Streptomycin. several post-screening analysis focusing on protein-ligand interaction has 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 Geometric analysis Comparing protein-ligand interactions by visually inspecting individual structures Becoming intractable when the number of complexes to be analyzed increasing Cluster analysis Represent and cluster candidates according to protein-ligand 3D information Needs meaningful representation of protein-ligand interactions.
Solubility of Molecule Drug Testing Gene Chips .– Drug molecule binds to cause biological effects – It is also called lock and key system – Structure determination of receptor is important Ligand-based drug design – Search a lead ocompound or active ligand – Structure of ligand guide the drug design process Identify Target Disease – Identify and study the lead compounds – Marginally useful and may have severe side effects Refinement of the chemical structures – Detect the Molecular Bases for Disease – Detection of drug binding site – Tailor drug to bind at that site – Protein modeling techniques – Traditional Method (brute force testing Genetics Review Overview Continued – A simple example Detect the Molecular Bases for Disease – Detection of drug binding site – Tailor drug to bind at that site – Protein modeling techniques – Traditional Method (brute force testing) Rational drug design techniques – Screen likely compounds built – Modeling large number of compounds (automated) – Application of Artificial intelligence – Limitation of known structures Refinement of compounds – Refine lead compounds using laboratory techniques – Greater drug activity and fewer side effects – Compute change required to design better drug Quantitative Structure Activity Relationships (QSAR) – Compute functional group in compound – QSAR compute every possible number – Enormous curve fitting to identify drug activity – chemical modifications for synthesis and testing.
Bayesian nets.“Gene chips” allow us to look for changes in protein expression for different people with a variety of conditions. and sets of compounds which can be reacted with the scaffold to place different structures on “attachment points”.000 compounds a day for activity against a protein target • Maybe tens of thousands of these compounds will show some activity for the protei • The chemist needs to intelligently select the 2 . Kahonen nets – Train with compounds of known activity – Predict activity of “unknown” compounds – Scoring methods – Profile compounds based on properties related to target – Fast Docking – Rapidly “dock” 3D representations of molecules into 3D representations of proteins. peptides or natural products instead of small molecules (chemistry) • Pioneered by biotechnology companies • Biopharmaceuticals can be quicker to discover than traditional small-molecule therapies • Biotechs now paring up with major pharmaceutical companies High-Throughput Screening • Drug companies now have millions of samples of chemical compounds • High-throughput screening can test 100.3 classes of compounds that show the most promise for being drugs to follow-up Computational Models of Activity • Machine Learning Methods – E. and to see if the presence of drugs changes that expression • Makes possible the design of drugs to target different phenotypes Biopharmaceuticals • Drugs based on proteins. • Usually involves a “scaffold” molecule. Neural nets.g. and score according to how well they bind Combinatorial Chemistry • By combining molecular “building blocks”. SVMs. • Molecular Modeling 3D Visualization of interactions between compounds and proteins “Docking” compounds into proteins computationally 3D Visualization . we can create very large numbers of different molecules very quickly.
Povl. Ulf. using computational models In Silico ADME Models • Computational methods can predict compound properties important to ADME. Krogsgaard-Larsen. Boston  Tollenaere JP (April 1996). – LogP.g. Tommy (2002). or in silico. Claude (1996). e.00 5.000-10. References  Madsen. Textbook of Drug Design and Discovery. as well as surfaces • Stereoscopic visualization available Docking” compounds into proteins computationally • In Vitro & In Silico ADME models • Traditionally. Washington. Liljefors. DC: Taylor & Francis  Cohen.X-ray crystallography and NMR Spectroscopy can reveal 3D structure of protein and bound compounds • Visualization of these “complexes” of proteins and potential drugs can help scientists understand the mechanism of action of the drug and to improve the design of a drug • Visualization uses computational “ball and stick” model of atoms and bonds. N. "The role of structure-based ligand design and molecular modelling in drug discovery" . time consuming and ethically undesirable • ADME (Absorbtion. helping reduce “atrittion” – the failure rate of compounds in late stage Size of databases • Millions of entries in databases – CAS : 23 million – GeneBank : 5 million • Total number of drugs worldwide: 60. Guidebook on Molecular Modeling in Drug Design. Distribution.000 • Fewer than 500 characterized molecular targets Potential targets : 5. Metabolism. a liphophilicity measure – Solubility – Permeability – Cytochrome p450 metabolism – Means estimates can be made for millions of compouds. However. animals were used for pre-human testing. animal tests are expensive. Excretion) techniques help model how the drug will likely act in the body • These methods can be experemental (in vitro) using cellular tissue.
Andrew R.Computational Biology and Chemistry  Gohlke H. "LigBuilder: A Multi-Purpose Program for Structure-Based Drug Design"  Schneider G.. "Further development and validation of empirical scoring functions for structure-based binding affinity prediction  Deng Z. Berlin: Springer. Singh J (January 2004). Chuaqui C. Lai L. Pharmacophore Perception. Calif: International University Line  Leach. Chuaqui C. and use in Drug Design. "Knowledge-based scoring function to predict protein-ligand interactions"  Deng Z. Stein V (April 2009). Development. Structure-based Drug Discovery. "SPORCalc: A development of a database analysis that provides putative metabolic enzyme reactions for ligand-based drug design".Gao Y. Hendlich M.Lai L (2000). Singh J (January 2004). (2000). Fechner U (August 2005). Harren Jhoti (2007). "Structural interaction fingerprint (SIFt): a novel method for analyzing three-dimensional protein-ligand binding interactions  Wang R. La Jolla. Wang S (January 2002).  Wang R. Klebe G (January 2000). "Computer-based de novo design of drug-like molecules". "Structural interaction fingerprint (SIFt): a novel method for analyzing three-dimensional protein-ligand binding interactions" . Osman F. Guner. Nat Rev Drug Discov  Smith J.
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue reading from where you left off, or restart the preview.