Rule of three

Congreve, M., Carr, R., Murray, C., Jhoti, H. A rule of three for fragment-based lead discovery Drug Discov. Today 2003, 8, 876-877. 

Another assessment of drug-likeness is afforded by Jorgensen s Qikprop family of ADME models [36]. In addition to the individual predictions, Jorgensen has proposed a rule-of-three. This proposes that a successful drug will have predicted... 

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

Consider a second example. A surgeon devises a new method of carrying out a surgical procedure and pilots the technique in 10 patients of which none suffer a post-operative infection. Can he claim therefore that the new technique is safe The answer again is no because in this case the upper end of the 95% confidence for the true infection rate is 0-26 % so that infection rate could be as high as one in four. (Hanley and Lippman-Hand developed a simple approximation for the 95% confidence for cases in which the observed data are of the form 0 out of n. They show that approximately the interval is 0-3 / n %. This is known as the rule of three. 

Rule of Three" Decreasing % B by 10% Increases capacity factor, k, by a factor of 3. 

The rule of three states that the capacity factor for a given solute increases approximately threefold when the organic phase increases by 10%. In Figure 25-12, tm = 2.7 min. Find k for peak 5 at 50% B. Predict the retention time for peak 5 at 40% B and compare the observed and predicted times. 

Prud homme, M. 1920. Rule of Three Temperatures. J. Chim. Phys. 18, 359. 

Table 3.1 Comparison of rule of three (R03)l7] with criteria for compounds of reduced complexity and for lead-like compounds.l27]...

Rule of three Lead-like Reduced complexity... 

M. Congreve, R. Carr, C. Murray and H. Jhoti A Rule of Three for fragment-based lead discovery, Drug Discov. Today, 8, 876-877 (2003). 

The ChemBridge collection of 5213 compounds was rationally selected from their EXPRESS-Pick Collection,181 utilizing Astex s rule of three considerations (MW < 300, HBD<3, HBA<3, CLogP<3)[12] and measures of diversity. ChemBridge has used a predicted aqueous solubility of greater than 3 mM for all selected compounds and can be... 

In discussing the appearence of diastereoselectivity in natural systems, the rule of three-point contact is frequently used11). This rule implies that a prochiral substrate becomes a chiral one, when it is fixed on three nonidentical points on the enzyme system. On the other hand, the well-known lock-key model is mainly based on a specific spacial arrangement and does not take into account specific types of bonding to the matrix12). For a discussion of diastereoselectivity in reactions with metal complexes, it seems more appropriate to use such a lock-key model. 

Women in business talk about the rule of three you need to have three women in any group in order for it not to be too biased in the male direction with respect to looking at female candidates, for it to be receptive to issues that are of traditional concern to women, and for a women in a group to get a hearing for her ideas. 

It can be directly derived from the rule of three functions (see below. Section 2.2.7) that three substrates (it might suffice that these are different enantiomers or diastereomers) correspond to three enzymes which can be distinguished in both functional and chemical terms. For each essential element, there thus must be at least four substances (three solid or dispersed/membrane-attached enzymes and the very speciation form of the essential element in dissolved or atmospheric (N, O, C, H, S) states) in the organism or directly linked to it in the enviromnent (soil, water, food, for photoautotrophs also the atmosphere (CO )). Living beings share one more property with traditional multiphase systems the... 

A multitude of different and closely matching biocatalytic functions which also means that a new function to be established during evolution or ontogeny will not necessarily - not even as a rule -imply integration of yet another heteroelement (cp. the number of functional proteins in some highly organized creature - often many thousands - to that of available elements - less than 40 - and recall the rule of three functions ). Rather the rule of three functions will limit functionalization of heteroelements (cp. Chapter 4). 

Although it was that simple to derive the rule of three functions in biochemistry in general, this modification cannot be calculated as straightforwardly because the reduction of autocatalytic order due to oligomerization depends sensitively on (bio-)chemical network topology. In addition to topological aspects of feedback in the network, the exact kind (manner) of dimerization which interconnects identical metal ions needs to be known, likewise the way by which the substrate interacts with this multimetal center (for example, the Mo dimerization effect is also seen with Mo-dependent nitrogenases but and the other reduc-... 

---