Structure & Ligand-Based Drug Design: Common Strategies
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Structure in drug discovery
The benefits of using the three-dimensional structure in structure and ligand-based drug design became evident during the early days of protein X-ray crystallography (Blundell et al. 2006). Two classic examples include the discovery of the AIDS drugs Agenerase and Viracept, developed using the crystal structure of HIV protease (Lapatto et al. 1989, Miller et al. 1989), and the influenza drug Relenza, designed using the structure of neuraminidase (Varghese, 1998). However, at that time, most pharmaceutical companies were not convinced. They deemed the method too costly and time-consuming for industrial application, thus relegating the responsibility of structure-based drug discovery research to academic institutions. The image on the right outlines the strategies and related services packages that can be considered for structure-based drug design.
How to plan a project?
Analyzing the information available for the target in question is crucial to kicking off a discovery project. The diagram above illustrates the diverse drug discovery and design project strategies.
- Protein structure known / ligand known – structure-based drug discovery (SBDD) is straightforward.
- Known protein structure / unknown ligand – virtual screening, fragment library screening, etc.
- Protein structure unknown / ligand known – possible to use ligand-based drug discovery techniques.
- Protein structure unknown / ligand unknown – de novo design, fragment library screening, high-throughput screening, etc.
The details of these options will be discussed below.
A project strategy should be defined before starting the drug discovery and design project, considering the availability of structural data on the protein and its ligands. The image briefly outlines the different options. For more details, please refer to the text.
Additionally, in several blog posts we discuss the applications of structural biology in drug discovery, starting from hit identification to structure-based drug discovery.
Structure-based drug discovery & design
The blue quadrant offers the most straightforward approach, leveraging the structures of both a ligand and the protein target for efficient structure-based drug discovery (SBDD). The structure of the bound ligand allows for the construction of a pharmacophore model, enabling the application of computational methods, virtual screening of fragments and larger compound libraries, and assessment of compound binding using docking methods. Our services also provide the option to screen compounds using biophysical methods or our proprietary weak affinity chromatography (WAC™) technology.
Upon identifying new hits, we verify binding details using the protein-ligand complex structure determined by X-ray crystallography or NMR spectroscopy. Hit identification, lead generation, and optimization necessitate repeated cycles of X-ray structure determination of the target protein with bound compounds. SAR (Structure-Activity Relationships)- based methods analyze and compare multiple hits and play a crucial role during lead optimization. Our services are tailored to deliver optimal and efficient performance independently of the specific nature of the project.
In the green quadrant, we focus on cases where we know the protein structure but not the ligand structure. In these situations, we conduct compound library screens. Our services include virtual and fragment screening (weak-affinity chromatography, WACTM ) and biochemical and biophysical assays to confirm the binding of the compounds. Once we identify suitable binders, we may develop a SAR model and clone, express, purify, and crystallize the protein in a complex with the best binders. This approach validates the binding mode, provides direct insights into the stabilizing interactions in the protein-ligand complex, and facilitates structure-based discovery and design methods. It’s important to note that the presence of a ligand at the binding site of the protein often facilitates the crystallization of a protein.
The yellow quadrant relates to ligand-based drug design, where the structure of the ligand is already known (e.g., a substrate or an inhibitor), but the structure of the protein target is unknown. In this scenario, we utilize a method called ligand-based drug design. The known ligand structure can create a pharmacophore model based on the ligand’s shape and electrostatics/polarity profile. This model can then be applied to screen a chemical library to select similar compounds and conduct QSAR analysis. Computational chemistry methods can also be employed for scaffold hopping and fragment replacement to generate new binders and potentially new IPs, if necessary. With advancements such as AlphaFold, it’s even possible to use a predicted protein structure to create a pharmacophore model for virtual screening in the early stages.
Having a known target structure significantly accelerates the drug discovery process. In the yellow and pink quadrants, it’s best to initiate the project by determining the protein structure using X-ray crystallography or NMR spectroscopy, followed by determining the structure of a ligand complex. Our gene-to-structure services package facilitates this process.
Gene-to-structure services
FastLane™ structures for drug discovery
In fragment-based drug discovery and design (FBDD), our services pipeline offers two essential steps:
- Fragment screening & hit identification
- Hit to lead generation and optimization
The most direct approach for designing entirely new compounds (green quadrant) would involve identifying hits using Fragment-Based Drug Discovery (FBDD) methods. We mainly utilize our proprietary weak affinity chromatography (WAC™) technology for this. The screening process can either use our fragment library or the libraries provided by our clients. The screening and subsequent activity assays are conducted with our collaborator, Red Glead Discovery. Additionally, we may evaluate the binding of the identified compounds using biophysical methods such as NMR spectroscopy, thermal-shift assays, or X-ray crystallography.
If the target protein’s experimental structure is unavailable, SARomics Biostructures provides gene-to-structure services. The protein is cloned, expressed, purified, and crystallized in such cases, and its X-ray crystallographic structure is determined. Detailed information on the crystallography process can be found in our learning center.
Hit to lead & lead optimization
At SARomics Biostructures, the service package, which includes hit-to-lead and lead optimization, is run in close collaboration with Red Glead Discovery. After identifying an active fragment (or fragments), further optimization of the interactions with the target protein (hit expansion & lead generation) is made to obtain more efficient binders. This is substantially easier when the three-dimensional structure of the protein target is known. Multiple protein-ligand complexes and SAR modeling of the compounds provide detailed mapping of the binding site, which is used in designing new compounds. Hit-to-lead optimization typically requires several cycles. The result may be a series of compounds, which will generate the final lead after further optimization and testing.
SARomics Biostructures’ integrated drug discovery and structure-based drug discovery services are adapted to each project’s needs and customer requirements. Please do not hesitate to contact us to discuss your project.
