Drug discovery Lipinski's Rule: what is it?

@morphism I'm sorry, not all the text is included

@morphism

What is most important in the context of quadruplex-binding ligands is to pay especial attention to:

1.

Minimization of ligand molecular weight. Aiming for compounds that approach the Lipinski limit of 500 daltons is clearly desirable since this can only improve uptake, although there are many examples of significantly larger molecules that are efficiently transported into cells.

2.

Optimization of permeability and uptake. Small molecules targeting telomeric or promoter quadruplexes have to transverse both the outer and the nuclear membranes. Ideally log P and pKreported. It is notable that none of these compounds fully complies with the Rule of Five. For example, the polycyclic acridine compound RHSP4 (Cookson et al., 2005) has the advantage of a low molecular weight and is readily taken up into the nuclei of a wide range of cancer cells (see Chapter 6) in spite of its relatively poor log P score. Other large polycyclic ligands carrying several positive charges such as BRACO-19 (3⁺) and the porphyrin TMPyP4 (4). It is plausible, though not proven, that their uptake is facilitated by an active transport mechanism in view of the high polarity of these compounds. However, their high charge hinders their ability to penetrate large tumor masses, so optimizing the lipophilic/lipophobic balance in a compound and monitoring log P values remains an important objective.

 

@morphism Here is a more accurate link to the study  https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/lipinskis-rule-of-five

3.

Avoidance of groupings that are readily metabolized, as well as those having inherent chemical instability. Ester groups can be cleaved by cellular esterases (unless this is part of a strategy to deliver a pro-drug or they are in sterically highly hindered positions). Ketones can be enzymatically reduced to hydroxyl groups. Amide groups can be cleaved by proteases. This is a potential concern since many G-quadruplex ligands have been developed over the past 12–14 years containing amide groups adjacent to phenyl rings (in order to extend the extended aromatic surface with minimal extra molecular weight cost). In many instances it appears that the close proximity to phenyl rings provides steric hindrance to proteolysis, but this cannot always be assumed. Methyl groups on aromatic systems can be oxidized to carboxylic acids. Aromatic nitro and amine groups can also be metabolized to toxic species, and should be avoided if possible. The presence of reactive alkylating groups such as activated epoxides can result in eventual cell death or even long-term carcinogenesis. The presence of phenolic or alcoholic hydroxyl groups can also be problematic since they can be conjugated to form glucuronides that are more polar and hence more readily cleared by the liver—this may sometimes be exploited to enhance the clearance of a highly non-polar compound.

4.

Avoidance of groups that may be overtly toxic to a cell, for example certain metals such as nickel or lead, or thiol groups.

5.

Off-target toxicity. This has not been reported, at least in publicly available documentation, for quadruplex ligands. It is a fair assumption that systematic screening in a range of neurological and cardiac-relevant assays has been undertaken for those few compounds that have undergone pre-clinical development, notably RHPS4, AS1410 and quarfloxin. Avoidance of even a low level of inhibition of the hERG potassium ion channel is especially important since hERG inhibition has been implicated in a drug-induced fatal cardiac arrhythmic syndrome and regulatory authorities now specifically request data from an hERG assay. An IC₅₀ value for hERG of >30 μM is considered acceptable, indicating a likely low propensity for cardiac off-target effects.

@antony10 That's a LOT 😀  Thanks, I will check it.

@antony10 Thanks for the interesting answer!

@morphism 👍 

@antony10 😉