2 research outputs found
Fighting Obesity with a Sugar-Based Library: Discovery of Novel MCH-1R Antagonists by a New Computational–VAST Approach for Exploration of GPCR Binding Sites
Obesity is an increasingly common
disease. While antagonism of
the melanin-concentrating hormone-1 receptor (MCH-1R) has been widely
reported as a promising therapeutic avenue for obesity treatment,
no MCH-1R antagonists have reached the market. Discovery and optimization
of new chemical matter targeting MCH-1R is hindered by reduced HTS
success rates and a lack of structural information about the MCH-1R
binding site. X-ray crystallography and NMR, the major experimental
sources of structural information, are very slow processes for membrane
proteins and are not currently feasible for every GPCR or GPCR–ligand
complex. This situation significantly limits the ability of these
methods to impact the drug discovery process for GPCR targets in “real-time”,
and hence, there is an urgent need for other practical and cost-efficient
alternatives. We present here a conceptually pioneering approach that
integrates GPCR modeling with design, synthesis, and screening of
a diverse library of sugar-based compounds from the VAST technology
(versatile assembly on stable templates) to provide structural insights
on the MCH-1R binding site. This approach creates a cost-efficient
new avenue for structure-based drug discovery (SBDD) against GPCR
targets. In our work, a primary VAST hit was used to construct a high-quality
MCH-1R model. Following model validation, a structure-based virtual
screen yielded a 14% hit rate and 10 novel chemotypes of potent MCH-1R
antagonists, including EOAI3367472 (IC<sub>50</sub> = 131 nM) and
EOAI3367474 (IC<sub>50</sub> = 213 nM)
Design and Application of a DNA-Encoded Macrocyclic Peptide Library
A DNA-encoded
macrocyclic peptide library was designed and synthesized
with 2.4 × 10<sup>12</sup> members composed of 4–20 natural
and non-natural amino acids. Affinity-based selection was performed
against two therapeutic targets, VHL and RSV N protein. On the basis
of selection data, some peptides were selected for resynthesis without
a DNA tag, and their activity was confirmed