Term
|
Definition
Less than:
500g/mol
10 proton aceceptors
5 proton donors
5 rotatable bonds
5 LogP |
|
|
Term
|
Definition
Less than:
10 rotatable bonds
12 proton donors and/or acceptors
140 angstrom^2 polar surface area |
|
|
Term
| Types of Intermolecular Forces |
|
Definition
dispersion
dipole dipole
hydrogen bonding
ionic -ionic (salt bridge)
ion-dipole
polar-pi interactions
aromatic pi stacking |
|
|
Term
|
Definition
Translates to the ability of a solvent to stabilize charge
Water = 80 ish DMSO = 47 Hexane = 2 |
|
|
Term
| Gibb's Free Energy (WRT ligand binding) |
|
Definition
G= H - TS
Enthalpy translates to IMFs and bond strengths
Entropy translates to the amount of states of a molecule/ electrostatics/ energy of solvation (drug into receptor). This value will increase with temperature increasing and lower in lower dielectrics |
|
|
Term
| Sum of Gibbs Free Energies (WRT ligand binding) |
|
Definition
| total binding energy = immobilizing the ligand + restricting rotors + binding enthalpy + H-bonding energies + ionic bond energies |
|
|
Term
| Relationship of Gibb's Free Energy to Keq |
|
Definition
| 1.36 kcal/mol change in Delta G is a factor of 10 change in Keq |
|
|
Term
|
Definition
c-c: sp3 = 1.54 A, sp2 = 1.47 A, sp = 1.37 A
c-H: sp3 to sp = about 1.1 A |
|
|
Term
|
Definition
Sp = 180
Sp2 bent = 120/119
Sp3 = 109.5
Sp3 bent = 104.5
Sp3 = 107.5 |
|
|
Term
|
Definition
FC = V - (N + B/2)
V valence electrons
n non bonded electrons
B bonded electrons |
|
|
Term
|
Definition
Ability of an electron cloud to distort in response to a dipole/charge (Inverse to the electonegativity trend)
Better nucleophiles are more polarizable (ex. SH > OH) and sp3>sp2>sp |
|
|
Term
| Bond Dissociation Energies |
|
Definition
CH3F>CH3OH>CH3NH3
110, 92, 85 kcal/mol respectively
Short to long bonds in this trend
C-C(sp), C-C(sp2), C-C(sp3)
200, 146-151, 83-85 kcal/mol respectively
C-H(sp), C-H(sp2), C-H(sp3)
132, 110, 105 kcal/mol respectively |
|
|
Term
|
Definition
4n+2 electrons for aromaticity
-must be flat
-must be conjugated
-must be cyclic |
|
|
Term
| Electron Donors/Acceptors |
|
Definition
Good donors = lonepairs > bonding pairs > carbanion > nitrogen > oxygen > halogens > CH/CR bond
Acceptors = are polarized C-R bonds (C-F is the best) CF>CO>CN>CC |
|
|
Term
|
Definition
Creates the association of organics in water (the most important force on molecular recognition in biological systems) Creates micelles which causes large enthalpy barrier to put a water molecule inside this micelle
aggregation of organics in water increases entropy from over ordering of water (shell of hydration) which also causes more favorable water-water enthalpic interactions but entropy drives this process still |
|
|
Term
|
Definition
Inductive
Electronegativity
Resonance
Ex. Methanol to phenol
Remember meta vs. para difference in pka
Electrostatic effects
Charges on mlcs will lower the pka of nearby complementary ionizable groups
Hybridization
Sp lowest pka
Solvation effects
Ex. MeOH vs tbuOH |
|
|
Term
|
Definition
1. When comparing neutral acids that make anionic CBs the most stable A- is the strongest acid
2. When comparing cationic acids the most stable HA+ is the weakest acid |
|
|
Term
| Organic Solvent Effects on pKa |
|
Definition
Organic solvents can’t handle built charge as well as water
This makes it so the pKa of acids go up in organic solutions |
|
|
Term
|
Definition
Swapping of atoms or groups of atoms produces a new stereoisomer
Already chiral at this center
Number of stereogenic centers per molecule = 2n-1
N = tetracoordinate stereogenic centers
Epimer
Stereoisomers that differ in configuration at only one center
Homochiral
Same overall sense of chirality but different molecules
Heterochiral
Opposite of homochiral |
|
|
Term
| Distinguishing Enantiomers |
|
Definition
Use a chiral salt to crystalize
Use a chiral column
Re-functionalize to make diastereomers |
|
|
Term
|
Definition
Diastereotopic H’s
Replacement of Ha or Hb leads to a diastereomer
Enantiotopic H’s
Replacement of Ha or Hb leads to an enantiomer
Pro-stereogenic centers
Pro-R or pro-S protons
Replace with the smallest mass unit higher
Homotopic groups can not be differentiated by chiral reagents
Enantiotopic groups can be differentiated by chiral reagents
Diastereotopic groups are differentiated by chiral and achiral reagents |
|
|
Term
| Quantum Mechanical Molecular Modeling |
|
Definition
based on: H psi = E psi (Schrodinger)
Examples = Ab initio which assigns 2 electrons at a time to MOs of increasing energy
Semiempirical QM:just uses valence electrons and approximates certain integrans with experimental data (can beat ab initio sometimes) Ex. AM1, PM3 and MNDO
Density-functional Theory - just optimizes electron densities ranter than wavefunctions |
|
|
Term
| Molecular Mechanics Molecular Modeling |
|
Definition
Molecule viewed as balls & springs
• Described by ball-and-spring U-functions
• E = ΣEstretch + ΣEbend + ΣEtorsion + ΣEVdW + ΣEelectrostatic + cross terms
Geometry Optimizations use this: use grid search wich rotates around torsional bonds in increments to find the lowest E (only get local minimum)
Ex. AMBER, CHARMm |
|
|
Term
| Molecular Dynamics Molecular Modeling |
|
Definition
Generates series of successive molecular
configurations by integrating Newton’s laws of motion forward in time.
Gives different conformations. Better chance to get a global minimum from this than MM. Adds energy to bonds while keeping MM force fields in mind to keep atoms together while optimizing energy of the conformations. |
|
|
Term
|
Definition
Assumptions:
1. All compounds in training series interact with same binding site in
same manner
2. Interactions responsible for critical effect noncovalent and enthalpic
3. Entropic terms vary minimally
between training series
compounds
Not included:
Solvent effects, diffusion/
transport factors
NEED NO INITIAL ACTIVE-SITE INFO. |
|
|
Term
|
Definition
Place each active/inactive inhibitor in a 3D grid
• Calculate steric and electrostatic interactions between atoms in molecule and probe atom placed at each grid point
• Need an array of activities and types of modifications to the core to assist in future SAR directions
Need to cross validate the CoMFA models to be predictive. |
|
|
Term
| Pharmacophore Mapping (QSAR) |
|
Definition
• generates search criteria to find new active
molecules in databases
• looking for something common (HB donors/acceptors, hydrophobic centers, and arrangements of these in 3D space) in all
actives and use db searching to find other
molecules that have it |
|
|
Term
|
Definition
| Involves the prediction of ligand conformation and orientation (or posing) within a targeted binding site. In general, there are two aims of docking studies: accurate structural modelling and correct prediction of activity. |
|
|
Term
|
Definition
| Electron densities of unit cells of molecules diffract X-rays at different incident angles (the larger the spread incident angles the better the resolution) Good resolution btw 0 and 3 angstroms. |
|
|
Term
|
Definition
| tells you how flexible the crystal structure is (high B equals more flexible and chance electron density can be off) |
|
|
Term
|
Definition
a comparison of the crystallographic electron density map to a model
Rfactor = (Rwork - Rfree)/Rwork
Rwork is the modeling data and Rfree is the electron density map. |
|
|
Term
|
Definition
Hanging drop or vapor diffusion methods:
will have to alter buffer, pH, precipitant (salts/organic solvents), temp and time to get a crystal. May have to chop off flexible parts, co-crystallize or put in a lipid-cubic phase if it is a membrane protein. |
|
|
Term
|
Definition
| Quantifies the amount of physiological response over a range of agonist addition (EC50) or antagonist addition (pA2) Gives the efficacy of the molecule. |
|
|
Term
|
Definition
| Determines the percent specific binding to a target (ex. Radiolabeled assay, SPR, ITC) |
|
|
Term
|
Definition
| Determines the pA2 (the negative log of the concentration of antagonist that requires that the dose of agonist be doubled to achieve a constant effect) by obtaining multiple EC50 values in the presence of different concentrations of inhibitor. Final plot is Log(DR-1) vs. -Log[I] and DR is EC50 with antagonist/EC50 without antagonist. |
|
|
Term
|
Definition
1.Association of the receptor with the ligand to form and the RL complex is a bimolecular process
2. The RL complex is reversible
3. All receptors of a given class are equivalent and
there is no cooperativity
4. Biological response is dependent on the attainment
of equilibrium between R and L
5. Response elicited by receptor occupancy is directly proportional to the number of receptors occupied (100% occupation leads to 100% response) |
|
|
Term
|
Definition
Two state "linear" receptor model
Allosteric Ternary Complex model
Cubic Ternary Complex Model
Extended Ternary Complex Model |
|
|
Term
|
Definition
Both Non-Competitive and Irreversible: The activity slowly goes down to zero with increasing amounts of inhibitor
Inverse Agonist. Gives an opposite response. Will look like a antagonist if the assay is not done correctly (normally concentration dependent) |
|
|
Term
|
Definition
| Ligand binds to the receptor and prompts binding of the G protein. The GDP bound to the G alpha domain is switched out for GTP and the proteins dissociate. The alpha subunit then can bind to other proteins such as adenylate cyclase to make cAMP signaling molecule. This reaction requires ATP. The GTP bound to the alpha sub-unit is dephopshprylated and then re associates with the beta gamma sub-units of the G protein. Cholera Toxin actually blocks this last GTP to GDP transformation which creates over active G alpha protein. |
|
|
Term
|
Definition
| 3 Families (A-C): All contain 7 transmembrane portions. Most ligands either bind to the extracellular N terminus (Family B/Glucagon Receptors) or between TM6,5,3, and 7. |
|
|
Term
|
Definition
| Ligand binding can induce GPCR kinases to phosphorylate the internal C terminus which induces Beta Arrestin binding which will then internalize by endocytosis. This can then either be recyclized (this is the desensitization mechanism) or degraded in the Lysosome. Protein made in the ER... |
|
|
Term
| GPCR Secondary Messengers |
|
Definition
| cGMP, cAMP, inostitol 1,4,5-triphosphate (IP3), and Diacylglycerol (DAG) |
|
|
Term
| Tyrosine Kinase Receptor Function |
|
Definition
| Ligand binds to the Extracellular N terminus and promotes dimerization. Then the c terminus is autophosphorylated and then proteins with an SH2 domain bind which either activate the enzyme or transcription factor leading to a cellular response. |
|
|
Term
| Dimerization of Tyrosine Kinase Receptors |
|
Definition
| Can have a bifunctional monomeric ligand that binds to both N-termini. Can have a Dimeric ligand that requires two ligands that each bind to each other and the proteins. Some proteins such as the insulin receptor are alreacy dimers (through disulfide bonds) and the ligand just activates the complex. |
|
|
Term
| Types of Tyrosine Kinase Drugs |
|
Definition
Agonists: Dimerized small ligands that mimic the natural ligand, allosteric activators, small ligands that stabilize a receptor-dimer interface. Direct activators of the catalytic domain, direct activators of the signal transduction pathways.
Antagonists/inhibitors: ligand blocking antibodies, small monomeric ligands that block access to one of the binding sites, allosteric inhibitors, small dimeric ligands that stabilize an unproductive receptor. Direct catalytic site inhibition (ex. Gleevec). Direct inhibition of the signal transduction pathways. |
|
|
Term
| Nuclear Receptor Superfamily |
|
Definition
-Receptors located in the cytoplasm or nucleus
-Regulate DNA transcription through the interaction with specific DNA sequences called hormone responsive elements (HRE).
•-Receptors directly interact with a variety of proteins
– Coactivators – e.g. histone acetyltransferases
– Corepressors – e.g. histone deacetylases |
|
|
Term
| Nuclear Receptor Structure |
|
Definition
| N-terminus, DNA binding domain (Zn fingers), hinge region, ligand binding domain, c-terminus. |
|
|
Term
| Nuclear Receptor Subgroups |
|
Definition
| Steroid Hormones (Class I), Vitamin/Thyroid Hormones (Class II), Metabolic Intermediates, and Xenobiotic Receptors (SXR and CAR) |
|
|
Term
|
Definition
Class I = Hormone binds to NR/Heat shock protein complex and removes the HSP. NR/hormone dimerizes and enters the nucleus through a specific nuclear pore. A coactivator and RNA polymerase then binds to the dimer and transcribes the target gene mRNA.
Class II = Hormone enters the nucleus through a nuclear pore and binds to the NR to displace the corepressor. Then the RNA polymerase and coactivator binds to transcribe the target gene mRNA. |
|
|
Term
| Ligand Gated Ion Channels |
|
Definition
| 4TM - n and c terminus extracellular and ligands bind in the intermembrane portion (ex. acetylcholine receptors), 3TM - Binds to the extra cellular N terminus and pacmans into the TM, 2TM (calcium/sodium channels) |
|
|
Term
|
Definition
| Relationship of potency to lipophilicty (pi), electronegativity (sigma), sterics, and other entropic constants. |
|
|
Term
|
Definition
| Determination of LogP by using functional group constants of lipophilicity. (CH3 = 1.5pi and -0.2pi per branched chain) |
|
|
Term
| Serine Protease Catalytic Mechanism |
|
Definition
| Ser, His, Asp catalytic triad mechanism with an activated H2O molecule release. |
|
|
Term
|
Definition
| truncation of an active sequence to find the active set of AAs, alanine point mutations to determine to R groups that are important, use of D-amino acids, insertions and deletions of AAs, cyclizing to lock in poses (decreasing entropic cost to binding) |
|
|
Term
| Peptide Amide Bond Isosteres |
|
Definition
| Peptoids = R groups moved to nitrogens of the amides, Carbamates, Ureas, Vinylogous peptides, Vinyl fluoride |
|
|
Term
|
Definition
| 5-aza cytidine, interferes with overmethylation by DNA methyl transferase in cancer cells. Aza blocks methylation |
|
|
Term
|
Definition
| CF2 replacement of phosphoether bond (pka similar to ether bond) methylene more stable but not good pka comparison. Nucleoside triphosphates normally to reduce the cost of phosphorylation (rate limiting) |
|
|
Term
| Sources of New Chemical Space |
|
Definition
| Competitor's compound, Natural Products, Endogenous Ligand, HTS, vHTS, structurally enabled compounds |
|
|
Term
| Ligand vs. Structure Based Design |
|
Definition
Ligand based = CoMFA uses shape/pharmacophore based, superimposition of actives
Structure based = Docking and scoring to find similar structures, need X-ray or HNMR structure |
|
|
Term
| Carboxylic Acid Isosteres |
|
Definition
| Tetrazole, hydroxamic acid, sulfonamides, sulfonylureas, Isothiazoles |
|
|
Term
|
Definition
| Ketone, CF3 replacement of carbonyl, oximes, oxadiazole, triazole, oxazole |
|
|
Term
|
Definition
| Swapping functionalities on a core of a drug or lead to attempt to create new IP or find a new pharmacophore. |
|
|
Term
|
Definition
| thiourea, squaricurea, cyanoguanadine |
|
|
Term
|
Definition
| 1H-Indazole, imidazol-2-one, oxazol-2-one |
|
|
Term
|
Definition
| Thiadiazole, pyrazine, triazine, pyridaine |
|
|
Term
|
Definition
| methylthiophene, cyclopropane, bicyclo[1.1.1]pentane, pyridine |
|
|
Term
| GI Epithelial Cells Absorption/Info |
|
Definition
Apical side (lumen side/inside of tract) of the epithelial cells absorb most drugs (high cyp concentration) in the duodenum (pH 4-7). Also, contains UFTs and many transporters
Basolateral side = portal vein side |
|
|
Term
|
Definition
ABC - ATP dependent (ex. P-glycoprotein, MRP) SLC - counterion facilitated (OAT, OCT, PEPT)
Saturation of these transporters is possible when [substrate] > Km (can cause drug-drug interactions) |
|
|
Term
| Bile Conjugate Transporters |
|
Definition
| P-glycoprotein (ABCB1), Multi-drug resistante protein (MRP), Organic anion trasporter protein (OATP1A2) |
|
|
Term
|
Definition
| ABCB1 - apical side (efflux transporter), transports hydrophobic or cationic compounds. Substrate specificity overlaps with CYP3A4 = lots of anti-proliferative drugs |
|
|
Term
|
Definition
| Organic anion/cation transporter proteins which uptake what it sounds like they do ( OAT ex. rifapimicin increases bioabalibility of prevastatin, OCT ex. acetylcholine) |
|
|
Term
|
Definition
| Peptide transporters and penicillins (apical side) uptake transporters ex. PEPT1 |
|
|
Term
|
Definition
| Formulation can control where in the GI tract the drug is released to take advantage of the variable uptake transporters/efflux transporters in the tract (needs to be highly potent to not saturate uptake transporters) |
|
|
Term
|
Definition
| Multi-drug resistant efflux pump (apical epithelial side) abacovir and other antiviral/cancer agents) |
|
|
Term
| Peptide Racimase Mechanism |
|
Definition
| PLP dependent mechanism (lysine bound in the enzyme) |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| Noncompetitive Inhibition |
|
Definition
|
|
Term
|
Definition
| LE = -deltaG/ # of heteroatoms |
|
|
Term
| Excretion and Absorption Anatomy pH Levels |
|
Definition
Stomach = 1.4-3
Duodenum = 5-7
Jejunum = 7.5-8
Urine (kidneys) = 4.5-8 |
|
|
Term
|
Definition
| Acids can be largely ionized (pH in urine 4-8) or unionized depending on the pH of the urine. Unionized weak acids promotes readsorption back into the blood in the kidneys (follows the concentration gradient). Giving NaHCO3 can increase the urine pH to promote the ionized form of the drug and block the readsoprtion. The opposite can be useful for very weak bases (treatment with ascorbic acid or ammonium chloride). |
|
|
Term
|
Definition
| Increases absorption (drug goes out of stomach to the gut) about every 6h. Increased by increased food intake, increased liquids, high protein diet, stress, prokinetic drugs |
|
|
Term
|
Definition
| alpha-acid glycoprotein binds basic drugs and albumin binds acidic drugs (and basic ones). Plasma protein binding can largely effect bioavailability. |
|
|
Term
| Phase II Metabolic Conjugation Reactions and cofactors |
|
Definition
| Methyl Transferases (SAM), Sulfotransferases aka. SULT (PAPS), Glutathione S-transferases aka. GST (Glutathione), UDP-glucouronosyl transferases aka. UGT (UDPGA), Acetyltransferase (AcCoA) |
|
|
Term
| Phase I Metabolic Reactions and cofactors |
|
Definition
| CYP monooxygenases (H2O, O2 NADPH, NADPH reductase), FMOs (NADPH, FAD, O2), Alcohol Dehydrogenases [Zn metalloenzyme(NAD+)], Aldehyde Dehydrogenase (NAD+, H2O), Aldehyde Oxidase (FAD, H2O, O2, Mo catalytic center), Monoamine oxidases (FAD, H2O, 1, 2, 3 amines selectivity) |
|
|
Term
| Monooxygenase Catalytic Cycle |
|
Definition
|
|
Term
|
Definition
Class 1-high permeability, high solubility
Class 2-high ", low "
Class 3-low ", high "
Class 4-low ", low "
Class 2 drugs efflux transporter effects dominate, class 3 uptake transporter effects dominate, Class 4 both efflux and/or uptake transporters can be important |
|
|
Term
| GI Tract Absorption Factors |
|
Definition
| Contains: peptidases, pGP efflux (high mw weak bases), gut bacteria. pH can vary throughout the tract, gastric emptying, blood flow can change, uptake transporters (ex. PEPT1 and penicillins) |
|
|
Term
| Main GI Tract transporters |
|
Definition
Efflux: PGP, MRP2 (GAs, Sulfates, GSHs), BCRP
Uptake: PEPT1 (dipeptides) OCT and OAT (organic cat/anions) |
|
|
Term
| Determination of BSC Classes |
|
Definition
Permeability: perfusion of intestines or Caco-2 cell bilayers (role of transporters can be determined by detecting apical vs. basolateral flux)
Absorption: fraction of dose excreted in urine (radiolabeled experiments of F=AUC oral/AUC IV) |
|
|
Term
|
Definition
V = amount of drug in body/[steady state blood]of drug
V = (FxD)/Co |
|
|
Term
| Enterohepatic Circulation |
|
Definition
| Drugs taken up by the liver can pass through the canalicular membrane into bile and re-enter the small intestine (mainly conjugates) |
|
|
Term
|
Definition
Weak Acids:
Carboxylic Acids 3-4, phenols 9-10, thiols 7-8, Imines 8-9, sulfonamides 5-6, enols 4-5
Weak Bases:
Amines 9-11, Aromatic amines 4-5, indoles 1, pyrimidine 1, anilines 5 |
|
|
Term
|
Definition
|
|
Term
|
Definition
CLr=(CurinexV)/Cplasma
and accounting for other factors
Clr = fraction unbound in protein x GFR + Rate of secreation/Cp - rate of readsorption/Cup |
|
|
Term
|
Definition
-readsoprtion happens by simple passive diffusion [high drug] and secretion is normally by active transport (conjugates and endogenous like substrates)
-if Clr/Fup > GFR then active secretion is dominant and vice versa |
|
|
Term
|
Definition
-active transport of high MW/GA conjugates
-substrates are normally polar with MW from 300-500 g/mol |
|
|
Term
|
Definition
Cp = Cp(initial)e^(-kt) where Cl/V = k
also t1/2 = 0.693(V)/Cl
-data from a LogCl vs Time plot |
|
|
Term
| Enzymatic Reaction Progress Curve Example |
|
Definition
|
|
Term
| Michaelis–Menten Misc. Info. |
|
Definition
Kcat*[E] = Vmax
Kcat/KM = specificity constant and defines the enzyme efficiency and selectiveness for a set of substrates
V = Vmax[S]/(KM+[S]) |
|
|
Term
|
Definition
(pka) = 1(11)>2(10)>3(9)>NH4(9)
inductive stabilization of ammonium in the tertiary amines make it a better acid = lower pka and a worse base. |
|
|
Term
|
Definition
| thymidine synthase mechanistic inhibitor. Blocks hydride abstraction with F. Can be deactivated by DPD (dehydrogenase) by reducing the double bond. Uracil can competitively block this. Prodrug = 4-amide ->deaminase->phosphorylase(drops sugar) |
|
|
Term
|
Definition
| TS inhibitor of adenosine deaminase, sp3 hydroxyl mimic of TS with an extra carbon to create a stable mlc. |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| Calicheamicin DNA cleavage |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| Bohlmann-Rahtz Pyridine Synthesis |
|
Definition
|
|
Term
| Bischler–Napieralski Reaction |
|
Definition
|
|
Term
| Cyclic Amine pka Alterations |
|
Definition
|
|
Term
| Tiffeneau-Demjanov Rearrangement |
|
Definition
|
|
Term
| Aza-Cope/Mannich Reaction |
|
Definition
|
|
Term
|
Definition
-blocks translation of RNA and can signal proteins to chop up RNA
-must modify nucleotides in order to resist nucleases (2'-fluoror, phosphorothioate) |
|
|
Term
|
Definition
-20 to 30 nucleotides
-Agos bind doublestranded siRNA bind and one half is lost, complementary RNA strands bind and are cleaved up by the Ago protein
-have to deliver as a viral or non-viral vector (unstable) |
|
|
Term
|
Definition
-Single strands (20 to 100 bps) of mainly RNA, sometimes DNA, that form unique 3D structures in solution
-act like antibodies that target protein- protein interactions
-Not immunogenic but unstable
-High mass PEGylation to up MW will avoid renal filtration and excretion
-SELEX technique to PCR a bunch of random bps and can chop off the primers then screen a massive library to find ones that dock |
|
|
Term
| Recombinant Protein Therapies |
|
Definition
| Ex. insulin. Proteins over-expressed in another organism. May fold wrong and have bad activity. |
|
|
Term
|
Definition
| Recombinant (in vitro) or monoclonal (in vivo) Can be used as drug conjugates. Must be very potent drugs due to low levels of drug concentration available. |
|
|
Term
|
Definition
| Ex. DARPins (repeat domain protein scaffolds) and Affibodies (derived from Beta domain of immunoglobulin) small portion of antibody loops that can act the same as antibodies |
|
|
Term
|
Definition
| ex. standard deviation. How much scores devieate from a mean (measures the spread of a distribution |
|
|
Term
|
Definition
Ex. t-test, ANOVA, two-way ANOVA, PCA
-t-test diffenetiates btw two groups on some variable of interest ex. do men and women have diffeent time spent sleeping
-paired t-test is for a before and after on the same group
-ANOVA can test the variance in data on more than 2 groups
-two-way ANOVA can test two or more variables on two groups (ex. two drugs and two sets of different mice)
-PCA find similarities of two groups on a large array of different readouts (ex. used in metabolomics of diseased state metabolites and control) |
|
|
Term
|
Definition
-low activity leads to sensitive biophysical binding experiments ex. DSF, ITC, SPR, MS NMR, X-ray (Binding does not equal efficacy though)
-grow target or link multiple frags based on binding pose
-Rule of 3 instead of rule of 5
-Can tether to a protein using disulfide ligands if a cystine is in the binding pocket and then do MS-MS
-use of Ligand Efficiency |
|
|
Term
|
Definition
| or Rapid elimination of swill filter used to cut out aggregators, fluorescent cmpds, and alkylating agents. Ex. exocyclic alkenes on heterocycles, a,b-unsaturated ketones, tetrahydroquinolines, diazyne, thiophenes, 2-aminothiophene-3-carboxylic acids, cathetols, quinones |
|
|
Term
|
Definition
| differential scanning fluorimetry which uses SYPRO Orange which binds to hydrophobic surfaces and water quenches its fluorescence. The unfolding of the protein exposes more hydrophobic surfaces and increases fluorescence. Used to see if ligands change the temperature at which the protein unfolds to show binding |
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Term
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Definition
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Term
|
Definition
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Term
|
Definition
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Term
|
Definition
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Term
|
Definition
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Term
|
Definition
|
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Term
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Definition
-His (6.04), Arginine (12.48), Lysine (10.54), Glu (4.07), Asp (3.90), Cys (8.37), Tyr (10.46)
-COO-(1.8-2.5), NH3+ (9.1-10.7) |
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Term
| All AAs Single Letter Codes |
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Definition
G - Glycine (Gly)
P - Proline (Pro)
A - Alanine (Ala)
V - Valine (Val)
L - Leucine (Leu)
I - Isoleucine (Ile)
M - Methionine (Met)
C - Cysteine (Cys)
F - Phenylalanine (Phe)
Y - Tyrosine (Tyr)
W - Tryptophan (Trp)
H - Histidine (His)
K - Lysine (Lys)
R - Arginine (Arg)
Q - Glutamine (Gln)
N - Asparagine (Asn)
E - Glutamic Acid (Glu)
D - Aspartic Acid (Asp)
S - Serine (Ser)
T - Threonine (Thr) |
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Term
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Definition
| GENERATE LIBRARY ->vHTS->HTS-> CONFIRM HITS ->orthogonal assays-> PICK SCAFFOLD (introduce other chemical matter here as well) ->optimize analogues-> LEADS ->analogue further for PK/PD analogue -> CANDIDATES |
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Term
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Definition
-ability to knockdown genes in cell culture (RNAi, CRISPR-Cas9), bioinformatic/data mining is necessary to make use of the genetic data
-Used to ID new pathways involved in disease, new targets, and new patient populations
-problem is that diseases can be poly-genic |
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Term
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Definition
| -find SNPs or regions where SNPs cause disease as a marker. Also, CYP phenotyping can show weak or strong metabolizers of drugs so one can correctly dose and avoid drug-drug interactions |
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Term
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Definition
-DNA microarrays to ID disease state patterns in genome wide expression levels (mRNA levels that must be confirmed by qPCR)
-RNA-seq is the new version of this (determines the transcriptome)
-Crispr-Cas9 can create SNPs or knockouts to confirm genetic target(s) |
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Term
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Definition
-affinity columns
-Direct acivity probes
-SILAC = heavy labeled cultures
-ICAT = biotin labled linker (cystine reactive)
-ITRAQ = isobaric tags (MS-MS shows quantitative protein exspression in multiple test groups, amino terminus reactive tag) |
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Term
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Definition
-LC-MS of cell lysates (spun down) of control and test groups
-use of PCA stats to find similarities and differences of metabolites in the groups
-goal to find bio-marker or cause of disease |
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Term
| Cross Species Variation in CYPs |
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Definition
| Diffference in CYPs expression levels, Difference in catyltic activity of CYP isoforms, and altered CYP regioselectivity in isoforms on the same metabolites |
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Term
| CYP monoocygenase Rate Limiting Step |
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Definition
| the single electron reduction (the second one) |
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Term
| Thiazolidine-2,4-dione Toxicity Mechanism |
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Definition
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Term
| Thiophene and alpha-ketothiophene toxicity |
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Definition
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Term
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Definition
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Term
| Phase II Induced Toxicity |
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Definition
-Acyl transfer of GA-carboxylic acid conjugates
-Glutathione (mustard like activation and thiotrichloroalkene toxicity)
-N-acyltransferase (Aromatic hydroxylamines)
-Sulfonyl transferase (aromatic hydroxyl amines and benzylic alcohol conjugates) |
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Term
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Definition
| -avoid acid breakdown in the stomach, improve oral absorption, site-specific delivery, prolong half-life, overcome solubility issues, better shelf life, avoid side effects |
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Term
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Definition
| Esters, phosphate hemiaminal, nucleobases (go to triphosphate nucleosides) |
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Term
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Definition
| Adenine N1 (3.6), Thiamine N3 (9.8), Guanine N1 (9.5) N7 (2.2), Cytosine N3 (4.1) |
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Term
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Definition
| A tablet/drugs ability to dissolve in the stomach/GI tract |
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Term
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Definition
| The ability of a drug to pass through membranes LogD>0 at 7.4 pH can actively diffuse and less than 0 cannot |
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Term
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Definition
| blood flow through a membrane (important in intramuscular delivery) |
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Term
| First Pass Metabolism Effectors |
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Definition
-first pass enzyme inducers ex. Ethanol (CYP2E1)
-CYP3A4 inhibitors ex. grapefruit juice (furanocoumarins)
-Induction of P-glycoprotein or MRP2 (apical/cannicular side of liver which can induce enterohepatic cycling) Efflux pumps |
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