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High-performance liquid chromatography (HPLC),formerly referred to as high-pressure liquid chromatography,is a technique in analytical chemistry used to separate,identify,and quantify specific components in mixtures. The mixtures can originate from food,chemicals,pharmaceuticals,biological,environmental and agriculture,etc,which have been dissolved into liquid solutions.
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 activates or inhibits the function of a biomolecule such as a protein,which in turn results in a therapeutic benefit to the patient. In the most basic sense,drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. 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,biopharmaceuticals including peptides and especially therapeutic antibodies are an increasingly important class of drugs and computational methods for improving the affinity,selectivity,and stability of these protein-based therapeutics have also been developed.
In the physical sciences,a partition coefficient (P) or distribution coefficient (D) is the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a comparison of the solubilities of the solute in these two liquids. The partition coefficient generally refers to the concentration ratio of un-ionized species of compound,whereas the distribution coefficient refers to the concentration ratio of all species of the compound.
ADME is the four-letter abbreviation (acronym) for absorption,distribution,metabolism,and excretion,and is mainly used in fields such as pharmacokinetics and pharmacology. The four letter stands for descriptors quantifying how a given drug interacts within body over time. The term ADME was first introduced in the 1960s,and has become a standard term widely used in scientific literature,teaching,drug regulations,and clinical practice.
Lipinski's rule of five,also known as Pfizer's rule of five or simply the rule of five (RO5),is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would likely make it an orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997,based on the observation that most orally administered drugs are relatively small and moderately lipophilic molecules.
Affinity chromatography is a method of separating a biomolecule from a mixture,based on a highly specific macromolecular binding interaction between the biomolecule and another substance. The specific type of binding interaction depends on the biomolecule of interest;antigen and antibody,enzyme and substrate,receptor and ligand,or protein and nucleic acid binding interactions are frequently exploited for isolation of various biomolecules. Affinity chromatography is useful for its high selectivity and resolution of separation,compared to other chromatographic methods.
Column chromatography in chemistry is a chromatography method used to isolate a single chemical compound from a mixture. Chromatography is able to separate substances based on differential adsorption of compounds to the adsorbent;compounds move through the column at different rates,allowing them to be separated into fractions. The technique is widely applicable,as many different adsorbents can be used with a wide range of solvents. The technique can be used on scales from micrograms up to kilograms. The main advantage of column chromatography is the relatively low cost and disposability of the stationary phase used in the process. The latter prevents cross-contamination and stationary phase degradation due to recycling. Column chromatography can be done using gravity to move the solvent,or using compressed gas to push the solvent through the column.
Chiral column chromatography is a variant of column chromatography that is employed for the separation of chiral compounds,i.e. enantiomers,in mixtures such as racemates or related compounds. The chiral stationary phase (CSP) is made of a support,usually silica based,on which a chiral reagent or a macromolecule with numerous chiral centers is bonded or immobilized.
An amphiphile,or amphipath,is a chemical compound possessing both hydrophilic and lipophilic (fat-loving) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic compounds include surfactants. The phospholipid amphiphiles are the major structural component of cell membranes.
Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. These lead compounds undergo more extensive optimization in a subsequent step of drug discovery called lead optimization (LO). The drug discovery process generally follows the following path that includes a hit to lead stage:
Micellar liquid chromatography (MLC) is a form of reversed phase liquid chromatography that uses an aqueous micellar solutions as the mobile phase.
Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. It is estimated from the molecular structure before the substance is even synthesized and tested. A druglike molecule has properties such as:
High-performance thin-layer chromatography (HPTLC) serves as an extension of thin-layer chromatography (TLC),offering robustness,simplicity,speed,and efficiency in the quantitative analysis of compounds. This TLC-based analytical technique enhances compound resolution for quantitative analysis. Some of these improvements involve employing higher-quality TLC plates with finer particle sizes in the stationary phase,leading to improved resolution. Additionally,the separation can be further refined through repeated plate development using a multiple development device. As a result,HPTLC provides superior resolution and lower Limit of Detection (LODs).
Blood plasma fractionation are the general processes separating the various components of blood plasma,which in turn is a component of blood obtained through blood fractionation. Plasma-derived immunoglobulins are giving a new narrative to healthcare across a wide range of autoimmune inflammatory diseases.
A monolithic HPLC column,or monolithic column,is a column used in high-performance liquid chromatography (HPLC). The internal structure of the monolithic column is created in such a way that many channels form inside the column. The material inside the column which separates the channels can be porous and functionalized. In contrast,most HPLC configurations use particulate packed columns;in these configurations,tiny beads of an inert substance,typically a modified silica,are used inside the column. Monolithic columns can be broken down into two categories,silica-based and polymer-based monoliths. Silica-based monoliths are known for their efficiency in separating smaller molecules while,polymer-based are known for separating large protein molecules.
Lipophilic efficiency (LiPE),sometimes referred to as ligand-lipophilicity efficiency (LLE) is a parameter used in drug design and drug discovery to evaluate the quality of research compounds,linking potency and lipophilicity in an attempt to estimate druglikeness. For a given compound LiPE is defined as the pIC50 (or pEC50) of interest minus the LogP of the compound.
In medicinal chemistry,parallel artificial membrane permeability assay (PAMPA) is a method which determines the permeability of substances from a donor compartment,through a lipid-infused artificial membrane into an acceptor compartment. A multi-well microtitre plate is used for the donor and a membrane/acceptor compartment is placed on top;the whole assembly is commonly referred to as a “sandwich”. At the beginning of the test,the drug is added to the donor compartment,and the acceptor compartment is drug-free. After an incubation period which may include stirring,the sandwich is separated and the amount of drug is measured in each compartment. Mass balance allows calculation of drug that remains in the membrane.
Ligand efficiency is a measurement of the binding energy per atom of a ligand to its binding partner,such as a receptor or enzyme.
Chemoproteomics entails a broad array of techniques used to identify and interrogate protein-small molecule interactions. Chemoproteomics complements phenotypic drug discovery,a paradigm that aims to discover lead compounds on the basis of alleviating a disease phenotype,as opposed to target-based drug discovery,in which lead compounds are designed to interact with predetermined disease-driving biological targets. As phenotypic drug discovery assays do not provide confirmation of a compound's mechanism of action,chemoproteomics provides valuable follow-up strategies to narrow down potential targets and eventually validate a molecule's mechanism of action. Chemoproteomics also attempts to address the inherent challenge of drug promiscuity in small molecule drug discovery by analyzing protein-small molecule interactions on a proteome-wide scale. A major goal of chemoproteomics is to characterize the interactome of drug candidates to gain insight into mechanisms of off-target toxicity and polypharmacology.
Chiral analysis refers to the quantification of component enantiomers of racemic drug substances or pharmaceutical compounds. Other synonyms commonly used include enantiomer analysis,enantiomeric analysis,and enantioselective analysis. Chiral analysis includes all analytical procedures focused on the characterization of the properties of chiral drugs. Chiral analysis is usually performed with chiral separation methods where the enantiomers are separated on an analytical scale and simultaneously assayed for each enantiomer.
References
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- 1 2 3 "Klara VALKO | Professor | Ph D, D Sc | University College London, London | UCL | School of Pharmacy | Research profile".
- 1 2 "Chromatographic Determination of Molecular Interactions".
- 1 2 "Physicochemical and Biomimetic Properties in Drug Discovery: Chromatographic Techniques for Lead Optimization".
- ↑ "Klara's Skincare".
- ↑ "Separation Methods in Drug Synthesis and Purification".
- ↑ Ganzler, K.; Salgó, A.; Valkó, K. (December 26, 1986). "Microwave extraction. A novel sample preparation method for chromatography". Journal of Chromatography. 371: 299–306. doi:10.1016/s0021-9673(01)94714-4. PMID 3558551 – via PubMed.
- ↑ Valkó, Klára; Bevan, Chris; Reynolds, Derek (June 1, 1997). "Chromatographic Hydrophobicity Index by Fast-Gradient RP-HPLC: A High-Throughput Alternative to log P/log D". Analytical Chemistry. 69 (11): 2022–2029. doi:10.1021/ac961242d. PMID 21639241 – via CrossRef.
- ↑ Valko, Klara; Nunhuck, Shenaz; Bevan, Chris; Abraham, Michael H.; Reynolds, Derek P. (November 29, 2003). "Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol/water and immobilized artificial membrane lipophilicity". Journal of Pharmaceutical Sciences. 92 (11): 2236–2248. doi:10.1002/jps.10494. PMID 14603509 – via PubMed.
- ↑ Valkó, Klára L.; Nunhuck, Shenaz B.; Hill, Alan P. (March 29, 2011). "Estimating unbound volume of distribution and tissue binding by in vitro HPLC-based human serum albumin and immobilised artificial membrane-binding measurements". Journal of Pharmaceutical Sciences. 100 (3): 849–862. doi:10.1002/jps.22323. PMID 20891009 – via PubMed.
- ↑ D, Montanari; E, Chiarparin; Mp, Gleeson; S, Braggio; R, Longhi; K, Valko; T, Rossi (September 29, 2011). "Application of drug efficiency index in drug discovery: a strategy towards low therapeutic dose". Expert Opinion on Drug Discovery. 6 (9): 913–920. doi:10.1517/17460441.2011.602968. PMID 22646214. S2CID 2167988 – via pubmed.ncbi.nlm.nih.gov.
- ↑ Gordon, Laurie J.; Allen, Morven; Artursson, Per; Hann, Michael M.; Leavens, Bill J.; Mateus, André; Readshaw, Simon; Valko, Klara; Wayne, Gareth J.; West, Andy (February 29, 2016). "Direct Measurement of Intracellular Compound Concentration by RapidFire Mass Spectrometry Offers Insights into Cell Permeability". Journal of Biomolecular Screening. 21 (2): 156–164. doi: 10.1177/1087057115604141 . PMID 26336900.
- ↑ Kl, Valkó (October 25, 2016). "Lipophilicity and biomimetic properties measured by HPLC to support drug discovery". Journal of Pharmaceutical and Biomedical Analysis. 130: 35–54. doi:10.1016/j.jpba.2016.04.009. PMID 27084527 – via pubmed.ncbi.nlm.nih.gov.
- ↑ Valko, Klara Livia; Teague, Simon P.; Pidgeon, Charles (March 24, 2017). "In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery". ADMET and DMPK. 5 (1): 14–38. doi:10.5599/admet.5.1.373 – via pub.iapchem.org.
- ↑ Valko, Klara Livia; Ivanova-Berndt, Gabriela; Beswick, Paul; Kindey, Mark; Ko, Dorothy (June 16, 2018). "Application of biomimetic HPLC to estimate lipophilicity, protein and phospholipid binding of potential peptide therapeutics". ADMET and DMPK. 6 (2): 162–175. doi:10.5599/admet.544 – via pub.iapchem.org.
- ↑ "The use of biomimetic chromatography to predict acute aquatic toxicity of pharmaceutical compounds: Toxicological & Environmental Chemistry: Vol 104, No 1". doi:10.1080/02772248.2021.2005065. S2CID 244046500.
- ↑ Stergiopoulos, Chrysanthos; Tsopelas, Fotios; Valko, Klara (June 6, 2021). "Prediction of hERG inhibition of drug discovery compounds using biomimetic HPLC measurements". Admet & DMPK. 9 (3): 191–207. doi:10.5599/admet.995. PMC 8920097 . PMID 35300361.
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