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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
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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.
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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.
54:, is used to predict the solubility of a potential oral drug. This coefficient can be experimentally measured or predicted computationally, in which case it is sometimes called "cLogP". As the lipophilicity of ionizable compounds is strongly dependent of pH,
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Ghose AK, Viswanadhan VN, Wendoloski JJ (January 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".
177:). 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. Furthermore,
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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
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Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (March 2001). "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings".
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Duffy FJ, Devocelle M, Shields DC (2015). "Computational
Approaches to Developing Short Cyclic Peptide Modulators of Protein–Protein Interactions". In Zhou P, Huang J (eds.).
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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 (
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Solubility in both water and fat, as an orally administered drug needs to pass through the intestinal lining after it is consumed, be carried in aqueous
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pharmacology at a given concentration. When associated with low clearance, high potency also allows for low total dose, which lowers the risk of
30:. It is estimated from the molecular structure before the substance is even synthesized and tested. A druglike molecule has properties such as:
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is directly affected. The great majority of drugs on the market have molecular weights between 200 and 600
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Uetrecht J (January 2001). "Prediction of a new drug's potential to cause idiosyncratic reactions".
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and penetrate the lipid-based cell membrane to reach the inside of a cell. A model compound for the
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properties affect the usefulness of a designed molecule. However, several
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A traditional method to evaluate druglikeness is to check compliance of
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46:(a lipophilic medium-chain fatty alcohol), so the logarithm of the
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Smith GF (February 2011). "Designing drugs to avoid toxicity".
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for how "druglike" a substance is with respect to factors like
253:"Idiosyncratic drug reactions: past, present, and future"
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OSIRIS Property
Explorer: Prediction of druglikeness
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Current
Opinion in Drug Discovery & Development
97:Molecular weight: The smaller the better, because
58:logD, or a logP vs pH curve may be used instead.
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500:free drug-likeness and bioactivity calculator
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647:Quantitative structure–activity relationship
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184:Druglikeness is not relevant for most
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416:. Progress in Medicinal Chemistry.
48:octanol-water partition coefficient
426:10.1016/B978-0-12-381290-2.00001-X
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22:is a qualitative concept used in
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306:10.1016/S0169-409X(00)00129-0
204:Fragment-based lead discovery
337:10.1007/978-1-4939-2285-7_11
82:idiosyncratic drug reactions
56:the distribution coefficient
251:Uetrecht J (January 2008).
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329:Computational Peptidology
78:non-specific, off-target
602:Lipinski's rule of five
198:Lipinski's rule of five
115:Lipinski's Rule of Five
16:Concept in drug design
607:Lipophilic efficiency
179:first-pass metabolism
162:and thus potentially
92:lipophilic efficiency
42:cellular membrane is
294:Adv. Drug Deliv. Rev
673:Medicinal chemistry
622:New chemical entity
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175:biological activity
496:2020-12-18 at the
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534:Topics in
468:2014-08-27
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211:References
154:, such as
40:lipophilic
186:biologics
164:mutagenic
148:irritants
135:mutagenic
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494:Archived
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