“Druglikeness”的意思、由来-开放百科全书

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:

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.

Since the drug is transported in aqueous media like blood and intracellular fluid, it has to be sufficiently water-soluble in the absolute sense (i.e. must have a minimum chemical solubility in order to be effective). 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 membrane to reach the inside of the cell.

Based on one definition, 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 molecular weight of the molecule and has 20-70 atoms.^[5]

Substructures with known toxic, mutagenic or teratogenic properties affect the usefulness of a designed molecule. However, 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. Alkylnitro compounds tend to be irritants, and Michael acceptors, such as enones, are alkylating agents and thus potentially mutagenic and carcinogenic.^[6]

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). Simple rules are not always accurate and may unnecessarily limit the chemical space to search: many best-selling drugs have features that cause them to score low on various druglikeness indices.^[7] Furthermore, first-pass metabolism, which is biochemically selective, can destroy the pharmacological activity of a compound despite good druglikeness.

Druglikeness is not relevant for most biologics, since they are usually proteins that need to be injected, because proteins are digested if eaten.

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References

1. ^{{cite journal | author = Uetrecht J | title = Prediction of a new drug's potential to cause idiosyncratic reactions | journal = Current Opinion in Drug Discovery & Development | volume = 4 | issue = 1 | pages = 55–9 |date=January 2001 | pmid = 11727323 | doi = }}
2. ^{{cite journal | author = Uetrecht J | title = Idiosyncratic drug reactions: past, present, and future | journal = Chem. Res. Toxicol. | volume = 21 | issue = 1 | pages = 84–92 |date=January 2008 | pmid = 18052104 | doi = 10.1021/tx700186p }}
3. ^{{cite journal | vauthors = Lipinski CA, Lombardo F, Dominy BW, Feeney PJ | title = Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings | journal = Adv. Drug Deliv. Rev. | volume = 46 | issue = 1-3 | pages = 3–26 |date=March 2001 | pmid = 11259830 | doi = 10.1016/S0169-409X(00)00129-0 }}
4. ^{{cite book|vauthors=Duffy FJ, Devocelle M, Shields DC|editor1-last=Zhou|editor1-first=Peng|editor2-last=Huang|editor2-first=Jian|title=METHODS IN MOLECULAR BIOLOGY. Computational Peptidology|date=2015|publisher=Humana Press|location=New York|isbn=978-1-4939-2284-0|pages=250–1|chapter=Computational approaches to developing short cyclic peptide modulators of protein-protein interactions|doi=10.1007/978-1-4939-2285-7_11|pmid=25555728}}
5. ^{{cite journal | vauthors = Ghose AK, Viswanadhan VN, Wendoloski JJ | title = 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 = J Comb Chem | volume = 1 | issue = 1 | pages = 55–68 |date=January 1999 | pmid = 10746014 | doi = 10.1021/cc9800071 }}
6. ^{{cite journal | author = Smith GF | title = Designing drugs to avoid toxicity | journal = Prog. Med. Chem. | volume = 50 | issue = 1 | pages = 1–47 | date=February 2011 | pmid = 21315927 | doi = 10.1016/B978-0-12-381290-2.00001-X }}
7. ^{{cite web|url=http://pipeline.corante.com/archives/2012/03/26/whats_the_ugliest_drug_or_the_ugliest_drug_candidate.php |title=Archived copy |accessdate=2014-08-27 |deadurl=yes |archiveurl=https://web.archive.org/web/20140726171435/http://pipeline.corante.com/archives/2012/03/26/whats_the_ugliest_drug_or_the_ugliest_drug_candidate.php |archivedate=2014-07-26 |df= }}

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References

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