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Drug discovery hit to lead
 
 
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Early drug discovery
Drug discovery

In medicine, biotechnology and pharmacology, drug discovery is the process by which medication are discovered and/or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipity discovery....
 involves several phases from target identification to preclinical development. The identification of small molecule modulators of protein function and the process of transforming these into high-content lead series are key activities in modern drug discovery. The Hit-to-Lead phase is usually the follow up of high-throughput screening
High-throughput screening

High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry....
 (HTS). It includes the following steps:


Hit explosion
Following hit confirmation, several compound clusters will be chosen according to their characteristics in the previously defined tests.






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Early drug discovery
Drug discovery

In medicine, biotechnology and pharmacology, drug discovery is the process by which medication are discovered and/or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipity discovery....
 involves several phases from target identification to preclinical development. The identification of small molecule modulators of protein function and the process of transforming these into high-content lead series are key activities in modern drug discovery. The Hit-to-Lead phase is usually the follow up of high-throughput screening
High-throughput screening

High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry....
 (HTS). It includes the following steps:

Hit confirmation


The Hit confirmation phase will be performed during several weeks as follows:
  • re-testing: compounds that were found active against the selected target are re-tested using the same assay conditions used during the HTS.
  • Dose response curve generation: several compound concentrations are tested using the same assay, an IC50 or EC50 value is then generated
  • orthogonal testing: Confirmed hits are assayed using a different assay which is usually closer to the target physiological condition or using a different technology.
  • secondary screening: Confirmed hits are tested in a functional assay or in a cellular environment. Membrane permeability is usually a critical parameter.
  • chemical amenability: Medicinal chemists will evaluate compounds according to their synthesis feasibility and other parameters such as up-scaling or costs
  • Intellectual Property evaluation: Hit compound structures are quickly checked in specialized databases to define patentability
  • Biophysical testing: Nuclear magnetic resonance
    Nuclear magnetic resonance

    Nuclear magnetic resonance is the name given to a physical resonance phenomenon involving the observation of specific quantum mechanics magnetism properties of an atomic atomic nucleus in the presence of an applied, external magnetic field....
     (NMR), Isothermal Titration Calorimetry
    Isothermal Titration Calorimetry

    Isothermal titration calorimetry is a biophysics technique used to determine the thermodynamics parameters of interactions. It is most often used to study the binding of small molecules to larger macromolecules ....
    , dynamic light scattering, surface plasmon resonance
    Surface plasmon resonance

    The excitation of surface plasmons by light is denoted as a surface plasmon resonance for planar surfaces or localized surface plasmon resonance for nanometer-sized metallic structures....
     are commonly used to assess whether the compound binds effectively to the target, the stoïchiometry of binding and to identify promiscuous inhibitors.
  • Hit ranking and clustering: Confirmed hit compounds are then ranked according to the various hit confirmation experiments.


Hit explosion


Following hit confirmation, several compound clusters will be chosen according to their characteristics in the previously defined tests. An Ideal compound cluster will:
  • have compound members that exhibit a high afinity towards the target (less than 1 µM)
  • show chemical tractability
  • be free of Intellectual property
  • not interfere with the P450 enzymes nor with the P-glycoproteins
  • not bind to human serum albumin
    Serum albumin

    Serum albumin, often referred to simply as albumin, is the most abundant plasma protein in humans and other mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular compartments and body tissues....
  • be soluble in water(above 100 µM)
  • be stable
  • have a good druglikeness
    Druglikeness

    Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is. It is estimated from the molecular structure before the substance is even synthesized and tested....
  • exhibit cell membrane permeability
  • show significant biological activity in a cellular assay
  • not exhibit cytotoxicity
  • not be metabolized rapidly
  • show selectivity versus other related targets


The project team will usually select between three and six compound series to be further explorated. The next step will allow to test analogous compounds to define Quantitative structure-activity relationship
Quantitative structure-activity relationship

Quantitative structure-activity relationship is the process by which chemical structure is quantitatively correlation with a well defined process, such as biological activity or chemical reactivity....
 (QSAR). Analogs can be quickly selected from an internal library or purchased from commercially available sources. Medicinal chemists will also start synthetizing related compounds using different methods such as combinatorial chemistry
Combinatorial chemistry

combinatorics chemistry involves the rapid organic synthesis or the computer simulation of a large number of different but structurally related molecules....
, high-throughput chemistry or more classical organic chemistry
Organic chemistry

Organic chemistry is a discipline within chemistry which involves the science study of the structure, properties, composition, chemical reaction, and preparation of chemical compounds that contain carbon....
 synthesis.

Lead generation phase


The objective of this drug discovery phase is to synthesize lead compound
Lead compound

A lead compound in drug discovery is a chemical compound that has pharmacology or biological activity and whose chemical structure is used as a starting point for chemistry modifications in order to improve potency, selectivity, or pharmacokinetic parameters....
s, new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics
Pharmacokinetics

Pharmacokinetics is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism....
. This optimization is accomplished through empirical modification of the hit structure and/or by employing structure-based design if structural information about the target is available.

Lead optimization phase


See also

  • High-throughput screening
    High-throughput screening

    High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry....
  • Fragment-based lead discovery
    Fragment-based lead discovery

    Fragment-based lead discovery is a method used for finding lead compounds as part of the drug discovery process. It is based on identifying small chemical fragments, which may bind only weakly to the biological target, and then growing them or combining them to produce a lead with a higher affinity....
     (FBLD)
  • High-content screening (HCS)
  • Enzyme inhibitor
    Enzyme inhibitor

    Enzyme inhibitors are molecules that bind to enzymes and decrease their enzyme activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolism imbalance, many drugs are enzyme inhibitors....
  • Drug development
    Drug development

    Drug development or preclinical development is defined in many pharmaceutical companies as the process of taking a new chemical lead through the stages necessary to allow it to be tested in human clinical trials, although a broader definition would encompass the entire process of drug discovery and clinical testing of novel drug candida...
  • Pre-clinical development
    Pre-clinical development

    Pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and safety data is collected....
  • Drug design
    Drug design

    Drug design is the approach of finding medication by design, based on their biological targets. Typically a drug target is a key molecule involved in a particular metabolic or signalling Metabolic pathway that is specific to a disease condition or pathology, or to the infectivity or survival of a Microorganism pathogen....
  • Rational drug design
  • Drug metabolism
    Drug metabolism

    Drug metabolism is the metabolism of Medication, their biochemical modification or degradation, usually through specialized Enzyme systems. This is a form of xenobiotic metabolism....
  • Cheminformatics
    Cheminformatics

    Cheminformatics is the use of computer and Information science techniques, applied to a range of problems in the field of chemistry. These in silico techniques are used in pharmaceutical companies in the process of drug discovery....
  • Pharmaceutical company
    Pharmaceutical company

    The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies can deal in Generic drug and/or brand medications....


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