Pharmaceutical Cocrystal Discovery via 3D-SMINBR: A New Network Recommendation Tool Augmented by 3D Molecular Conformations

Cocrystals have significant potential
in various fields
such as
chemistry, material, and medicine. For instance, pharmaceutical cocrystals
have the ability to address issues associated with physicochemical
and biopharmaceutical properties. However, it can be challenging to
find proper coformers to form cocrystals with drugs of interest. Herein,
a new in silico tool called 3D substructure–molecular-interaction
network-based recommendation (3D-SMINBR) has been developed to address
this problem. This tool first integrated 3D molecular conformations
with a weighted network-based recommendation model to prioritize potential
coformers for target drugs. In cross-validation, the performance of
3D-SMINBR surpassed the 2D substructure-based predictive model SMINBR
in our previous study. Additionally, the generalization capability
of 3D-SMINBR was confirmed by testing on unseen cocrystal data. The
practicality of this tool was further demonstrated by case studies
on cocrystal screening of armillarisin A (Arm) and isoimperatorin
(iIM). The obtained Arm–piperazine and iIM–salicylamide
cocrystals present improved solubility and dissolution rate compared
to their parent drugs. Overall, 3D-SMINBR augmented by 3D molecular
conformations would be a useful network-based tool for cocrystal discovery.
A free web server for 3D-SMINBR can be freely accessed at http://lmmd.ecust.edu.cn/netcorecsys/.