Druglikeness is a qualitative concept used in drug design

Drug design

Drug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...

 for how "druglike" a substance is with respect to factors like bioavailability

Bioavailability

In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

. It is estimated from the molecular structure before the substance is even synthesized and tested. A druglike molecule has properties like this:

• Optimal solubility to both water and fat, because an orally administered drug has to go through the intestinal lining, carried in aqueous blood
  Blood
  Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
  
   and penetrate the lipid cellular membrane to reach the inside of a cell. The model compound for the cellular membrane is octanol
  Octanol
  Octanol is a straight chain fatty alcohol with eight carbon atoms and the molecular formula CH37OH. Although the term octanol usually refers exclusively to the primary alcohol 1-octanol, there are other less common isomers of octanol such as the secondary alcohols 2-octanol, 3-octanol and...
  
  , so the logarithm of the octanol/water partition coefficient
  Partition coefficient
  In chemistry and the pharmaceutical sciences, a partition- or distribution coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium. The terms "gas/liquid partition coefficient" and "air/water partition coefficient" are...
  
  , known as cLogP, is used to estimate solubility.
• Potency at the target of interest. High potency (high value of pIC₅₀
  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...
  
  ) is a desirable attribute in drug candidates, as it reduces the risk of non-specific, off-target pharmacology at a given concentration. When associated with low clearance, high potency also allows for low total dose, which lowers the risk of idiosyncratic drug reaction
  Idiosyncratic drug reaction
  Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the cause is not known...
  
  .
• Several scoring methods can be used to express druglikeness as a function of potency and physicochemical properties, for example 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...
  
  .
• Since the drug is transported in aqueous media like blood and intracellular fluid, it has to be sufficiently water-soluble in the absolute sense. Solubility in water can be estimated from the number of hydrogen bond
  Hydrogen bond
  A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
  
   donors vs. alkyl sidechains in the molecule. Low water solubility translates to slow absorption and action. Too many hydrogen bond donors, on the other hand, lead to low fat solubility, so that the drug cannot penetrate the cell wall to reach the inside of the cell.
• Molecular weight: The smaller the better, because diffusion
  Diffusion
  Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
  
   is directly affected. Eighty percent of traded drugs have molecular weights under 450 daltons
  Atomic mass unit
  The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
  
  ; they belong to the group of small molecule
  Small molecule
  In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
  
  s.
• Substructures that have known chemical or pharmacological properties.

A traditional method to evaluate druglikeness is to check compliance of Lipinski's Rule of Five

Lipinski's Rule of Five

Lipinski's Rule of Five is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. The rule was formulated by Christopher A...

, which covers the numbers of hydrophilic groups, molecular weight and hydrophobicity.

Arup Ghose reported that a drug-like molecule has a logarithm of partition coefficient (log P) between -0.4 and 5.6, molecular weight 160-480 g/mol, molar refractivity of 40-130, which is related to the volume and moelcular weight of the molecule and has 20-70 atoms.

Also, other factors such as substructures with known toxic, mutagen

Mutagen

In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...

ic or teratogenic

Teratology

Teratology is the study of abnormalities of physiological development. It is often thought of as the study of human birth defects, but it is much broader than that, taking in other non-birth developmental stages, including puberty; and other non-human life forms, including plants.- Etymology :The...

 properties affect the usefulness of a designed molecule. In fact, several poison

Poison

In the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....

s have a good druglikeness. Natural toxins are used in pharmacological research to find out their mechanism of action, and if it could be exploited for beneficial purposes.

Druglikeness indices are inherently limited tools. Druglikeness can be estimated for any molecule, and does not evaluate the actual specific effect that the drug achieves (biological activity

Biological activity

In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or pharmacophore but can be modified by the other...

). Furthermore, first-pass metabolism, which is biochemically selective, can destroy the pharmacological activity of a compound despite good druglikeness.

External links

• OSIRIS Property Explorer: Prediction of druglikeness
• molinspiration free drug-likeness and bioactivity calculator