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

Abstract

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/.

Network-Based Methods and Their Applications in Drug Discovery

“…Drug cocrystals can enhance the solubility, stability, and bioavailability of drugs. Several network-based methods have been developed to predict drug cocrystals and validated in several drugs, such as apatinib , and armillarisin A . In 2023, we proposed a new computational tool, named 3D-SMINBR (3D substructure-molecular-interaction network-based recommendation), to discover proper coformers to form cocrystals with drugs.…”

“…Then, 3D-SMINBR was applied in the cocrystal screening of two drug candidates, armillarisin A and isoimperatorin. After the experimental validation, armillarisin A–piperazine and isoimperatorin–salicylamide cocrystals were found to have elevated solubility and dissolution rate …”

“…Therefore, network-based methods have been widely applied in various types of biological molecules, including approved drugs, natural products, synthesized chemical entities, , complex TCM formulas, , and even peptides . Despite only performing simple mathematical operations such as matrix multiplication, network-based methods have shown high performance not only in the evaluation indicators but also in various application domains of drug discovery, such as mechanism elucidation, drug effect prediction, , property optimization, and precision medicine . Moreover, several web servers have been introduced for researchers to use network-based methods in drug discovery.…”