Target Structure Determination

Drug discovery relies on an accurate understanding of the molecular structure of the biological target during the target identification and verification phase. This understanding is helpful for the design of the lead compound structure in the subsequent phases. For many years, Ace Therapeutics has been focusing on the discovery of small-molecule targeted drugs in ophthalmology. Our talented structural biologists can provide high-quality structure determination services to resolve target structures to meet the needs of different customers, thereby accelerating the development of ophthalmic products.

The Necessity of Target Structure Determination

Drug development relies on accurate knowledge of the structure of organic molecules such as proteins, nucleic acids and viruses. Obtaining accurate 3D structural information about drug targets helps to define the topology of ligand-complementary surfaces and mode of action (MOA) studies to optimize drug potency and selectivity. Structure determination is the process of solving the three-dimensional atomic coordinates of biomolecules such as proteins and nucleic acids using one or more analytical techniques. Many techniques have been used for structure determination, the most common being X-ray crystallography, NMR spectroscopy, cryo-electron microscopy, and molecular modeling, and so on. Structure determination is widely applied to a set of targets. This includes extremely complex targets such as proteins and DNA, but also very simple molecules such as diatomic oxygen and nitrogen.

Fig. 1. The steps involved in X-ray crystal structure determination, from target selection to publication. (Berman H, et al., 2004)

Services Overview

Ace Therapeutics employs world-class facilities and state-of-the-art methodologies to provide you with sophisticated insights into biological targets and their interactions with compounds. As a comprehensive ophthalmology preclinical research CRO, our structural biologists can use one or more techniques to analyze the structure of different types of biological targets, such as proteins, nucleic acids, etc., which can provide valuable information for your subsequent drug design opinions to accelerate your ophthalmic small molecule drug discovery program.

Ace Therapeutics has the expertise and equipment to accurately determine the structure of thousands of ophthalmic target biomolecules. Our scientists have decades of analytical experience in structure determination. This provides you with reliable data that can be used throughout the ophthalmic small molecule drug discovery process to optimize ligand design and generate the most potent candidates.

Our Experience

X-Ray Crystallography

The key to the design of small-molecule targeted drugs in ophthalmology is to understand proteins related to human eye diseases, and X-ray crystallography is widely used to capture the three-dimensional structure of protein crystals. Ace Therapeutics has a dedicated team of X-ray crystallographic scientists to resolve high-resolution protein target structures. However, this technique requires the protein to be in a crystalline state and is not suitable for all protein analyses. Coincidentally, our cryo-electron microscopy (cryo-EM) can make up for this shortcoming.

Target Structure Determination

Cryo-Electron Microscopy

Cryo-electron microscopy (Cryo-EM), a technique that does not require crystallization, has become a major tool for elucidating the structure of target proteins, especially large proteins such as the membrane-bound proteins that make up most modern drug targets. It is now widely used in the drug discovery process. Our structural biologists can analyze large proteins and large protein complexes for you with the help of cryo-electron microscopy, and use their cryogenic imaging features to accurately identify drug targets, thereby guiding your development of small molecule targeted drugs.

To the delight of our clients, our talented structural biologists combine X-ray crystallography with cryo-EM where necessary. Cryo-EM can be used to generate images of protein complexes, and subsequent X-ray crystallography can allow for a detailed look at each protein individually. This helps speed up the drug development process.

NMR Spectroscopy

NMR spectroscopy can provide specific information about molecular dynamics, reaction states, structure and chemical states. The technique has been used to analyze the complete structure and conformation of complex molecules and for the quantitative analysis of complex mixtures. Ace Therapeutics can provide unrivaled NMR spectroscopy services for biophysical characterization, examining the Higher Order Structure (HOS) of products, including secondary and tertiary structure, oligomerization and aggregation.

Target Structure Determination

Molecular Modeling

Molecular modeling describes the generation, representation, and/or manipulation of 3-D structures of chemical and biological molecules, and the determination of physicochemical properties that help explain the structure-activity relationships (SARs) of biomolecules. When the structure of your target is unknown or cannot be determined experimentally (X-ray crystallography, cryo-EM or NMR), our structural biologists use molecular modeling, mainly homology modeling, to construct the 3D structure of your target. Utilize structure-based virtual screening and direct docking methods for potential drug molecules to understand target structures. In structure-based virtual screening, large databases of chemical structures are searched to identify potential drug candidates that are most likely to bind to drug targets.

For many years, Ace Therapeutics has been focusing on small-molecule targeted drug discovery in ophthalmology. Using multiple structure determination methods, our scientists can perform high-quality target structure determination services for the global customers. If you are interested in our services or need more detailed information, please feel free to contact us. We look forward to working with you.

References

Berman H, Bourne P, Westbrook J. The Protein Data Bank: A Case Study in Management of Community Data. Current Proteomics 2004;1(1).
Aminpour M, Montemagno C, Tuszynski JA. An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications. Molecules. 2019:30;24(9):1693.

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