Early drug discovery

Drug discovery

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous 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. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...

 (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
  IC50
  The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...
  
   or EC50
  EC50
  The term half maximal effective concentration refers to the concentration of a drug, antibody or toxicant which induces a response halfway between the baseline and maximum after some specified exposure time...
  
   value is then generated. Methods are being developed that may allow the reuse of the compound that generated the hit in the initial HTS step. These molecules are removed from beads and transferred to a microarray for quantitative assessment of binding affinities in a "seamless" approach that could allow for the investigation of more hits and larger libraries.
• 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 a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
  
   (NMR), Isothermal Titration Calorimetry
  Isothermal Titration Calorimetry
  Isothermal titration calorimetry is a physical technique used to determine the thermodynamic parameters of interactions in solution. It is most often used to study the binding of small molecules to larger macromolecules .-Thermodynamic measurements:ITC is a quantitative technique that can...
  
  , 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....
  
  , dual polarisation interferometry
  Dual Polarisation Interferometry
  Dual polarization interferometry is an analytical technique that can probe molecular scale layers adsorbed to the surface of a waveguide by using the evanescent wave of a laser beam confined to the waveguide...
  
  , microscale thermophoresis
  Microscale Thermophoresis
  Microscale Thermophoresis is a technology for the analysis of biomolecules. Microscale Thermophoresis is the directed movement of particles in a microscopic temperature gradient...
  
   (MST) are commonly used to assess whether the compound binds effectively to the target, the stoïchiometry of binding, any associated conformational change
  Conformational change
  A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
  
   and to identify promiscuous inhibitors.
• Hit ranking and clustering: Confirmed hit compounds are then ranked according to the various hit confirmation experiments.

Hit expansion

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 affinity towards the target (less than 1 µM)
• Moderate molecular weight and lipophilicity (usually measured as cLogP). Affinity, molecular weight and lipophilicity can be linked in single parameter such as ligand efficiency
  Ligand efficiency
  Ligand efficiency is a measurement the binding energy per atom of a ligand to its binding partner, such as a receptor or enzyme.Ligand efficiency is used in drug discovery research programs to assist in narrowing focus to lead compounds with optimal combinations of physicochemical properties and...
  
   and lipophilic efficiency
  Lipophilic efficiency
  Lipophilic efficiency , sometimes referred toas ligand-lipophilicity efficiency 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...
  
   to assess druglikeness
  Druglikeness
  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...
  
  
• 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 a protein that in humans is encoded by the ALB gene.Serum albumin is the most abundant plasma protein in mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular...
  
  
• 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 with respect to factors like bioavailability. 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
  Cytotoxicity
  Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
  
  
• 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 explored. The next step will allow to test analogous compounds to define Quantitative structure-activity relationship

Quantitative structure-activity relationship

Quantitative structure–activity relationship or QSPR is the process by which chemical structure is quantitatively correlated with a well defined process, such as biological activity or chemical reactivity.For example, biological activity can be expressed quantitatively as the concentration of a...

 (QSAR). Analogs can be quickly selected from an internal library or purchased from commercially available sources. Medicinal chemists will also start synthesizing related compounds using different methods such as combinatorial chemistry

Combinatorial chemistry

Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials...

, high-throughput chemistry or more classical organic chemistry

Organic chemistry

Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 synthesis.

Lead optimization 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 pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.Lead compounds are often found in...

s, new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics

Pharmacokinetics

Pharmacokinetics, sometimes abbreviated as PK, 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 chemical modification of the hit structure, with modifications chosen by employing structure-activity analysis (SAR) as well as structure-based design if structural information about the target is available.

See also