The CSD-Materials Suite provides a cohesive analysis of solid form properties for early-stage drug discovery


A complete interaction map (FIM) for the Cambridge Structural Database entry DEDMUX, a potential tuberculostatic agent. This FIM compares the observed intermolecular interactions to preferred geometries for this type of interaction. The red regions of the map denote areas where there is a high probability for a hydrogen bond acceptor, the blue regions denote hydrogen bond donors, and the brown regions indicate hydrophobic preferences. Photo credit: Ghazala Sadiq, CCDC Scientific Liaison and Senior Scientist

The existence of different molecular arrangements that occur in the solid is called polymorphism. During the early phase of drug discovery, researchers often study hydrogen-bonding networks to identify potential metastable polymorphs. But what if a system has no hydrogen bonding? Or what if the hydrogen bonding networks are the same in two different solid forms?

Go beyond hydrogen bonding networks with CSD materials

The Cambridge Crystallographic Data Center’s CSD Materials suite provides a comprehensive analysis of a potential active pharmaceutical ingredient (API), helping researchers to explore and analyze intra- and intermolecular interactions within the lattice. Along with Hydrogen Bond Propensity, the suite includes components with early-stage drug discovery applications, including Full Interaction Maps (FIMs) and an Aromatics Analyzer. These can prove particularly useful when hydrogen bonding networks cannot fully distinguish polymorphic stability.

Complete interaction maps (FIMs) highlight interaction preferences

FIMs provide a molecule’s interaction preferences in the context of the observed crystal structure and produce an intuitive 3-D visualization of the molecule’s preferred interactions and the intermolecular packing of the crystal structure. This can help identify potential co-former or solvent interactions for a new drug. The component calculates regions around the molecule where chemical probe groups are likely to be found, using the empirically derived, expert-curated data in the Cambridge Structural Database (CSD). The CSD is the worldwide archive for low molecular weight organic and organometallic crystal structures – with over 1.1 million structures from X-ray and neutron diffraction analyses.

Aromatics Analyzer identifies stabilizing interactions

The Aromatics Analyzer enables the quantitative assessment of interactions between aromatic rings and is the first component of CCDC to be based on a neural network. The model assesses the strength of an aromatic interaction between two phenyl rings using quantum mechanics and the relative positions of the rings, and highlights any likely contribution to the stability of a crystal structure. Sometimes the dominant interactions that stabilize a system are solvent dependent. The Aromatics Analyzer can help specifically in these cases, as well as when hydrogen bonding networks alone cannot distinguish between solid forms.

Case study: AstraZeneca uses CSD materials to reduce risk when choosing solid forms in the early phase of drug development

In a recent article in Crystal growing and designResearchers at AstraZeneca have applied the CSD Materials suite – specifically the Hydrogen Bond Propensity, FIMs and Aromatics Analyzer components – to mitigate the solid forms of a potential benefit for immune-mediated diseases.

In this work, the authors first analyzed the hydrogen bond networks of two solid forms using the Hydrogen Bond Propensity Tool. dr Okky Dwichandra Putra is a co-author of the article and Associate Principal Scientist in Early Product Development and Manufacturing at AstraZeneca.

“Typically, we observe that the propensity tool can differentiate between hydrogen-bonding propensities to indicate possible risks,” says Putra. “However, it is not uncommon for the slopes of hydrogen bonds to overlap. This also depends on the tilt ranges and how much they overlap. And the more complex the molecules get, the more competing sites for hydrogen bonding there are.”

Therefore, it is standard that the team also perform a dispersion-corrected density functional theory (DFT) calculation and that the team use the Aromatics Analyzer and the FIMs components of CSD-Materials. These methods were all used to analyze two key shapes in the work. Both the Aromatics Analyzer tool and the DFT calculations demonstrated the importance of considering aromatic interactions, particularly in the pharmaceutically most appropriate solid form.

“We found that stacking and other dispersion interactions play an important role in crystal structure stabilization and crystal growth,” says Putra. “Therefore, it is crucial to preserve the entire interactions described and not just hydrogen bonds.”

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More information:
Okky Dwichandra Putra et al, Understanding Crystal Structures to Guide Form Selection of Pharmaceutical Agents: A Case Study of AZD9567, Crystal growing and design (2021). DOI: 10.1021/acs.cgd.1c01124

Provided by CCDC – Cambridge Crystallographic Data Center

citation: The CSD Materials Suite Provides a Cohesive Analysis of Solid Shape Properties for Early Stage Drug Discovery (2022 March 15) Retrieved March 15, 2022 from -csd-materials-cohesive-analyse-solid-properties.html

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