Biomedical Engineering Reference
In-Depth Information
2.2 MCR PRODUCTS FOR HTS
2.2.1 MCRs and HTS: The Real and the Virtual
The most direct application of MCRs in DOS is to use MCR products directly for HTS.
This strategy carries the obvious advantage of executing a one-step synthesis that is
amenable to automation with simple liquid handling and subsequent purification.
Other immediate advantages include short time frames for scale-up and SAR studies.
Liabilities include structural diversity that is limited to variation in the appendages
of a single core structure as well as products that are usually racemic. MCRs are,
on the whole, difficult to render asymmetric by either auxiliary or catalyst control.
Racemic molecules are often viewed as an advantage for HTS in that they double the
chances for discovering a high-affinity ligand or otherwise biologically active small
molecule in an HTS experiment. That said, the discovery of activity immediately
requires the identification of the active enantiomer, which has required the use of
preparative chiral chromatography.
Many important discoveries in HTS are MCR products that are used directly or
with minimal modification in HTS. Although it is difficult to quantify, early screening
libraries from commercial vendors were based largely on the availability of small
molecules, to which single-step synthetic compounds, including MCR products,
contributed greatly. One prominent example is found in monastrol (
1
), a dihydropy-
rimidinone that is formed by the Biginelli reaction of urea,
m
-hydroxybenzaldehyde,
and ethyl acetoacetate. This compound was found to induce a “monoastral” pheno-
type in a microscopy-based phenotypic screen at Harvard Medical School's Institute
for Chemistry and Cell Biology (ICCB) using a library of compounds acquired from
commercial sources [5]. After this initial discovery, the active enantiomer was dis-
cerned [6], a co-crystal structure with the protein target (Eg5/MSK) revealed that
monsatrol bound in an unfavorable conformation [7], and a cyclic product that mim-
icked this state was revealed to have superior activity [8]. More recently, Priaxon,
an MCR-focused company engaged in drug discovery, identified compound
5
as one
of several inhibitors of the proteins HDM2 and p53 [9]. Compound
5
is formed
by a Shaw 4CR, followed directly by amide coupling. Priaxon has a stated focus
specifically on MCRs for the advantages that are conferred (i.e., ease of library syn-
thesis as well as subsequent follow-up studies) on the assumption that discovery time
lines will necessarily be shortened. Furthermore, their current repertoire of MCRs
enables access to (theoretically) 1
10
9
compounds, assuming reasonable reaction
efficiency for all available components [10]. Clearly, this number will grow with
the discovery of each new MCR. In addition to these two examples, several drugs
(approved or in development) have been synthesized by MCRs (Figure 2.1), including
the antihelminthic drug praziquantel [11] (
11
), GlaxoSmithKline's (GSK's) oxytocin
antagonist [12] (
12
), the antiplatelet agent clopidogrel [13] (
13
), and the antiandrogen
bicalutamide [14] (
14
).
The basic idea of accelerating discovery by focusing on MCRs in HTS has recently
been applied prospectively by linking docking or “virtual” screening to synthesis.
The use of computation to guide discovery ligands for protein targets
in silico
has
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