Rules:
No more than 5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen–hydrogen bonds)
No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms)
A molecular mass less than 500 daltons
An octanol-water partition coefficient[5] log P not greater than 5
But the drugs widely used (Streptomycin, Paromomycin, Amphotericin B) does not follow these rules at all. Then what is the use of these rules during virtual drug designing?? Are these just to add one more table in the publication :p ??
Dear Arushdeep,
The Lipinski's rule of five based on about 90% of the drugs' property ADME. The rule is applied only to permeation by passive diffusion of drugs through cell membranes; drugs that are actively transported through cell membranes by transporter proteins are exceptions to this rule.
in addition, there are many limitations to this rule. It is a metric that can predict drug-likeness, although biologicals parenterall drugs and many natural products are excluded from this rule.
Due to the rule simplicity it became an efficient tool in the design process. However, this rule should be used with a lot of caution and other sophisticated metrics should be utilized where appropriate.
For more details please see:
http://www.ncbi.nlm.nih.gov/pubmed/18035532
https://www.researchgate.net/publication/236731043_Open_Source_Software_and_Web_Services_for_Designing_Therapeutic_Molecules?ev=prf_pub
http://osddlinux.osdd.net/
Hoping this will be helpful,
Rafik
Article Open Source Software and Web Services for Designing Therapeu...
Dear Arushdeep,
Though lipinsky's rule of five offers a valuable tool to assess the drug likeliness there are two limitations for it:
1. It is applicable for only those drugs administered orally.
2. It is applicable only for those drugs which are absorbed through passive transport mechanisms.
You can also take into consideration; the Jogersen's rule of three.
Thank you !
i will have different perception regarding the lipiski rule of five.
Although i agree that this rule is applicable to most oral clinical drugs and directs the bioavailability (ADME) of candidate drugs in the biological system. But, sticking with it for common generalisation/application is not good for predicting lead compounds. As, few violation to this rule are very common.
QED sounds to be good enough to explain the similar phenomena.
Earlier, I have also done some work on protein targets druglikeness predictions (http://www.sciencedirect.com/science/article/pii/S1093326316302534)
The Lipinski rules are only statistical and no one can force you to follow them (especially, if you run your own pharma company). However, using them might spare you a lot of trouble at the lead optimization phase of your drug discovery project. It would be easier and less costly to obtain compounds with desired pharmacokinetic properties, if they follow Lipinski rules. Nevertheless, if you work with natural products (like the drugs you cite in your question) then it would be a totally different story and, indeed, you would not need to care about Lipinski rules (but it does not make this path easier to follow).
An interesting - but less discussed - side effect of Lipinski's rule of 5 is that chemical compounds within the boundaries can be reasonably handled in practice in the wet lab from synthesis, through purification, work-up, up to physchem, biology, pharmacology, clinics, thus, it roughly describes which chemicals that can be moved through the R&D funnels.
The far Lipinski rule outlier Amphotericin B is a good example where purification and analytical characterisation proved to be very difficult.
So it is not only a drug-likeness space, it is also a feasibility space the rules describe.
Being oversimplifying rules, not all compounds falling into the Lipinski space will become drugs nor will all successful drugs fall into the Lipinski space.
An important consideration is HOW to count hydrogen bond acceptors and donors. 1D or 2D can be often misleading and totally misregard intramolecular shielding effects. Some "violations" are not really violations but errors arising from level of theory applied.
The question finally comes down to WHICH drugs you want to design. Know your anticipated site of action and mode of action, then search for existing successful drugs and keep your new drug's physchem properties close to the known working space. This way you generate your own special purpose rules.
Dear, Arushdeep
Lipinski RO5 is a good parameter to weed out unwanted compounds from your compounds library. Keep in mind that, nowadays, many molecules on a chemical catalogue obey the RO5, so dont use it as the only parameter for compound selection.
Additionally you shouldn't rely so strictly on RO5 values since there are many examples of drugs on the market that dont obey the rule.
Finally, keep in mind that your compounds properties may be outside RO5 space but always check your project objective to adjust your molecules properties accordingly.
what if zero hydrogen bond acceptor or hydrogen bond donor, is it still acceptable in Lipinski's rule?
what rule or parameter should i follow to consider a compound to be a drug in future which is derived from suger or natural compound? i got two hits from molecular docking and simulation but confused about this.
"Lipinski explicitly warned in his paper that the Rule-of-5 does not apply to natural products." For example.
https://www.sciencedirect.com/topics/nursing-and-health-professions/lipinskis-rule-of-five
Bakary Ntji Diallo Hello, Your perspective what kind of filtering process I can use for natural products??
Sourav Biswas not really sure about that, maybe PAINS, ligand efficiency?
Ligand efficiency denotes the valance of Heavy atoms. So, from my perspective Toxicity is a good screening tool in terms of natural products.
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