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. 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 and penetrate the lipid cellular membrane to reach the inside of a cell. The model compound for the cellular membrane is octanol, so the logarithm of the octanol/water partition coefficient, known as cLogP, is used to estimate solubility.
• Potency at the target of interest. High potency (high value of pIC₅₀) 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.^[1][2]
• Several scoring methods can be used to express druglikeness as a function of potency and physicochemical properties, for example ligand efficiency and lipophilic efficiency.
• 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 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 is directly affected. Eighty percent of traded drugs have molecular weights under 450 daltons; they belong to the group of small molecules.
• Substructures that have known chemical or pharmacological properties.

A traditional method to evaluate druglikeness is to check compliance of Lipinski's Rule of Five, 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.^[3]

Also, other factors such as substructures with known toxic, mutagenic or teratogenic properties affect the usefulness of a designed molecule. In fact, several poisons 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). Furthermore, first-pass metabolism, which is biochemically selective, can destroy the pharmacological activity of a compound despite good druglikeness.

References

1. ^ Uetrecht, J. (2001). "Prediction of a new drug's potential to cause idiosyncratic reactions". Curr. Opin. Drug Disc. Devel. 4: 55–59. 
2. ^ Uetrecht, J. (2008). "Idiosyncratic Drug Reactions: Past, Present, and Future". Chem. Res. Toxicol. 21: 84–92. doi:10.1021/tx700186p. PMID 18052104. 
3. ^ Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. (1999). "A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases". Journal of Combinatorial Chemistry 1 (1): 55–68. doi:10.1021/cc9800071. PMID 10746014.  edit

External links

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

This pharmacology-related article is a stub. You can help Wikipedia by expanding it.v · Categories: Drug discovery Pharmacology Medicinal chemistry Pharmacology stubs Wikimedia Foundation. 2010. Игры ⚽ Нужно решить контрольную? Weißenstein Fluorogenic Look at other dictionaries: 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 …   Wikipedia Drug discovery — In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed. In the past most drugs have been discovered either by identifying the active ingredient from traditional… …   Wikipedia Partition coefficient — In chemistry and the pharmaceutical sciences, a partition (P) or distribution coefficient (D) is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium.[1] The terms gas/liquid partition …   Wikipedia Drug discovery hit to lead — Early drug 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… …   Wikipedia Drug design — Not to be confused with Designer drug. 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.[1] The… …   Wikipedia Quantitative structure-activity relationship — (QSAR) 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 in the… …   Wikipedia Chemical library — A chemical library or compound library is a collection of stored chemicals usually used ultimately in high throughput screening or industrial manufacture. The chemical library can consist in simple terms of a series of stored chemicals. Each… …   Wikipedia Lead compound — A lead compound (i.e. the leading compound, not lead metal) 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… …   Wikipedia Lipinski — is a Polish surname that may identify: *Adam Lipiński (1956 ), Polish politician. *Christopher A Lipinski, originator of Lipinski s Rule of Five to evaluate druglikeness *Dan Lipinski (1966 ), Polish American politician. *Dariusz Lipiński (1955 ) …   Wikipedia Lipinski's Rule of Five — Die Rule of Five (engl. für „5er Regel“) ist eine Faustregel für die orale Bioverfügbarkeit einer chemischen Verbindung. Sie wurde 1997 von dem Chemiker Christopher Lipinski aufgestellt. Lipinski stellte fest, dass viele gängige Arzneistoffe… …   Deutsch Wikipedia 18+ © Academic, 2000-2024 Contact us: Technical Support, Advertising Dictionaries export, created on PHP, Joomla, Drupal, WordPress, MODx. Mark and share Search through all dictionaries Translate… Search Internet Share the article and excerpts Direct link … Do a right-click on the link above and select “Copy Link”