How vast is the chemical space of RNA drugs?

Chemical space

By chemical space is meant the space spanned by all chemical compounds. As of January 2012, there are more than 64 million organic and inorganic substances reported in the scientific literature (link). This is, however, still only a vanishing fraction of the total number of possible small organic molecules, which has been estimated to exceed 1060 (read: 10 to the power of 60) (link). Drug discoverers have to navigate the mind-boggling vastness of this chemical space to identify those few compounds that can be used as drugs. In some cases, knowledge about the drug target and the chemistry involved in drug-target binding allows rational drug design principles to be applied. That is, drug space is truly navigated in the sense of purposeful steering. In many cases, as with for example high-throughput screening, however, the discovery process is more like drifting through space on a random-walk-like trajectory.

For the RNA drug subspace, sequence information allow us to estimate the number of possible oligos that can be designed against a given target. In this blog I will focus on oligos consisting of only DNA and LNA nucleotides. Also, I will consider only two types of general designs: gapmers against mRNA targets and mixmers against miRNA targets.

Gapmers

Gapmers are oligos that have a stretch of DNAs in the middle and LNAs in the flanks. A shorthand notation for a 10nt gapmer with 3 LNAs in each flank and 4 DNAs in the middle (the gap) is LLLDDDDLLL. When a gapmer oligo binds to the region of its RNA target transcript where it has perfect complementarity, the DNAs in the gap forms

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a DNA:RNA double cost viagra or cialis strand with the target transcript which can recruit RNAse H. Upon RNAse H binding the transcript is cleaved (link) and the cleaved fragments degraded by exonucleases.

So, for a given target, how many gapmers can be designed? Say that the transcript is n nucleotides long, and that the oligo is l nucleotides long. Then we can tile nl+1 oligos along the transcript. For n >> l, nl+1 is approximately equal to n. For example, a transcript that is 1000nt long can have 987 oligos of length 15 tiled along its length.

Concerning gapmer length, say that oligos between lmin and lmax in length are relevant to consider. That is, at each starting position, the oligo length can be between lmin and lmax, and there are therefore lmaxlmin+1 different lengths that needs to be evaluated. Also, several (k) gapmer designs may be relevant. For example, the number of LNAs in each flank may vary between 2 and 3, giving k=4 (e.g. LLDDDDLL, LLLDDLLL, LLDDDLLL, LLLDDDLL).

The total number of oligos then equals

{ Σ(nl+1) } × k , where the sum (Σ) is over l, from lmin to lmax

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p>For the example used here with a 1000nt transcript, oligos between 10nt and 20nt in length, and four different gapmer designs, the total number of oligos that can be designed is 43384. A simple approximation is to say that at each position in the 1000nt long transcript, we can cialis migraine design 11 × 4 = 44 different gapmers (varying length

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and design), giving 44000 in all.

Mixmers

A mixmer binding to a miRNA hinders the binding of the RISC-incorporated miRNA mature strand to its mRNA targets. Effectively, it can be seen as an antagonist to the miRNAs natural “ligands”. For a mixmer, DNA and LNA nucleotides are mixed to optimize binding affinity and transport. A 10nt mixmer could for example be written LDLDLDLDLL.

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p>In contract to gapmers, the length

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of the miRNA targets are usually only around 22nt in length – much shorther than the mRNA targets for gapmers. On the other hand, the possibility of mixing LNA and DNA in the oligos, make the number of different designs explode, as is shown in the following.

In its most simple form, for a mixmer of viagraonline-4rxpharmacy.com length l, where at each position we can have either a DNA or a LNA, the total number of possibilities is 2l. For a 10mer, for example, there are 210 = 1024 possibilities. Three design considerations constrain the possibilities: (1) There has to be at least one LNA in each flank to protect against degradation by endonucleases, (2) depending on the oligo length, the LNA/DNA ratio is usually constrained to a certain interval, e.g. between 20% and 80% for a 16mer, since both too high- and low affinity is unwanted, and (3) there should be no more than 3 DNAs in a row to avoid RNAse H recruitment.

I will skip the equations for the total number of possibilities under these constraints for now (perhaps a topic for a separate blog), and simply tabulate the possibilities for mixmers between 8nt and 23nt

8 2

9 16

10 74

11 92

12 352

13 1108

14 3024

15 7432

16 16862

17 39882

18 78280

19 152782

20 294270

21 567524

22 1091972

23 1053464

For this example I furthermore assumed that the seed portion (nucleotides 2-7 counting from the 5′-end) of the miRNA should be covered by the mixmer and that the LNA/DNA ratio interval went linearly from 100% LNA for 8mers to max 80% and min 20% for 23mers. All in all there are a bit more than 3.3 million possibilities. Notice that the even with these constraints, the number of mixmers that can be designed scales exponentially with the mixmer length.

Gapmer vs mixmer space

With design criteria as specified here, the number of gapmers that can be designed scales linearly with the length of the target mRNA, whereas the number of mixmers scales exponentially with the length of the mixmer. Perhaps surprisingly, this means that the mixmer space quickly becomes much larger than the gapmer space. For both mixmer and gapmer spaces, however, it seems reasonable that the number of oligos are <1010, even when allowing other nucleotide modifications besides LNA. This is still a relatively small number compared to small molecule compounds, where, just online pharmacy prescriptions for derivatives of n-hexane, for example, there are more than 1029 possibilities (Weininger, pp 425–530 in Encyclopedia of Computational Chemistry).

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One comment on “How vast is the chemical space of RNA drugs?
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3 Pings/Trackbacks for "How vast is the chemical space of RNA drugs?"
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