Structure-Activity Relationship (SAR) Optimization of Hits

Overview of Hit Optimization

The drug discovery process leading up to the preclinical phase unfolds through two distinct stages: hit identification and hit optimization. In the initial phase of target-to-hit, CD BioGlyco meticulously helps clients select a diverse array of glycan compounds displaying an affinity for the target from our DNA-encoded Glycan Library (DEGL). Wherein novel compounds, frequently unearthed through the methodology of High Throughput Screening (HTS), undergo a rigorous assessment to ascertain their viability for subsequent optimization towards lead candidates. After Hit & Analogues Synthesis and Hit Activity Verification, we conduct structure-activity relationship (SAR) optimization of hits, which is a pivotal stage within the realm of drug discovery, and concerns the transition from hit compounds to lead candidates.

Refine the Hits: Mastering SAR Optimization for Superior Drug Discovery

SAR Optimization by Direct Chemical Modification

In the stage of hit SAR optimization, CD BioGlyco intricately modifies each identified hit by adding novel functional groups, resulting in lead compounds that exhibit superior affinities compared to their hit predecessors. The central ambition of this phase is to metamorphose these "hit" entities into "lead" compounds endowed with enhanced pharmacological attributes, including but not limited to potency, selectivity, safety, and characteristics emblematic of drug-likeness. This critical phase effectively bridges the chasm separating the identification of promising initial candidates from developing lead candidates primed for rigorous lead optimization and preclinical advancement.

SAR Optimization by In Silico Methods

Besides, our research team uses sophisticated computational tools such as docking simulations, molecular dynamics simulations (MD), and artificial intelligence methods to conduct SAR optimization. Both the target-to-hit and lead optimization phases have witnessed marked improvements in efficiency, attributed to the use of these sophisticated computational tools. These innovations have played a pivotal role in streamlining the drug discovery process, fostering a more effective approach to lead compound development. Specifically, we employ auto in silico ligand directing evolution for the rapid investigation of the SAR in the optimization of hit compounds. This approach is adept at enhancing a lead compound through subtle chemical modifications to its scaffold, yielding minimal variations in ligand binding efficacy.

Workflow

We offer a comprehensive, end-to-end service encompassing the entire spectrum of drug discovery. This includes the meticulous Design of DEGL, the construction of these libraries, HTS, Next-generation Sequencing of HTS Outputs, the subsequent Data Analysis and Visualization, and Hit Validation and Assessment. Our integrated approach is engineered to advance the drug discovery process with high efficiency. By implementing systematic methodologies and detailed management, we ensure seamless transitions between each stage, thereby facilitating high-quality screening and optimization. This strategic framework is designed to significantly enhance progress in drug development for our clients.

Workflow of SAR optimization. (CD BioGlyco)

Workflow of Direct Chemical Modification

We aim to refine "hit" compounds, initially identified, into "lead" candidates with superior pharmacological profiles. The procedural steps include:

Undertake intensive SAR investigations to evaluate each compound's activity and selectivity meticulously.
Employ structure-based drug design techniques-such as molecular modeling, X-ray crystallography, and nuclear magnetic resonance (NMR)-to expedite and focus the SAR development.
Conduct a screening cascade to assess compound activity against the target molecule and identify potential selectivity issues.
Evaluate compound activity across various species, particularly in animal models.
Conducting detailed profiling of the physicochemical properties and in vitro absorption, distribution, metabolism, and excretion characteristics, including solubility, permeability, and microsomal stability (ADME).
Perform further structure modifications tailored to the client's specific needs to address compound deficiencies, optimizing SAR.
Finally, the optimized glycans must undergo a series of toxicity assessments and in vivo behavioral model tests to confirm their suitability.

Workflow of direct chemical modification. (CD BioGlyco)

Workflow of In Silico Methods

The auto in silico ligand directing evolution methodology hinges on MD simulations, which are augmented by a one-step free energy perturbation (FEP) technique. Upon receipt of an initial protein-glycan complex structure, we undertake SAR optimization through the following streamlined steps.

Execution of molecular dynamics simulations to assess the structural flexibility inherent to the protein-glycan complex.
Collection of a conformational ensemble that accurately captures the representative states of the protein-glycan complex.
Generation of glycan analogs employing a fragment-based growth methodology to transform the hit into derivative compounds.
Evaluation of binding free energy variations, facilitating the comparison between the protein-glycan and glycan-analog complexes. This process ultimately leads to the identification of promising lead compounds, prioritized according to their binding free energy modifications.

Publication Data

Technology: Hotspot analysis, Pocket pharmacophore prediction, Directory-based SAR optimization, Molecular docking, Machine learning (ML), Deep learning (DL) models

DOI: org/10.3389/fchem.2020.00093

Journal: Frontiers in Chemistry

Published: 2020

IF: 3.8

Result: In this study, authors research the in silico strategies for optimizing fragment-to-lead (F2L) transitions through computational methods, including hotspot analysis, pocket pharmacophore prediction, directory-based SAR optimization, molecular docking, and the application of ML and DL models in drug discovery. Initially, the authors introduce hotspot analysis as a structural tool for F2L optimization, aimed at predicting regions within binding sites that contribute maximally to binding free energy. The FTMap server is highlighted as a principal instrument for hotspot analysis, employing small organic probes to predict hotspot locations on protein surfaces. The example of B-RAF kinase is used to demonstrate how FTMap can be utilized to predict hotspots and refine fragment compounds, culminating in the development of the drug vemurafenib. The discussion progresses to pocket pharmacophore prediction, particularly addressing scenarios in fragment screening where binding sites are not well-defined. Pocket pharmacophore prediction aids researchers in identifying the most promising pharmacophoric sites, thus facilitating subsequent stages of the F2L process. Additionally, the paper covers directory-based SAR optimization methods, which enable rapid and cost-effective F2L optimization through the search for similar compounds. Molecular docking is extensively used to predict the binding modes and energies of small molecules with proteins. In F2L optimization, it is often combined with other techniques to increase the likelihood of transforming fragment compounds into high-affinity ligands. Finally, the authors explore the role of machine learning and deep learning models in F2L optimization. These models, by analyzing large datasets, develop quantitative SAR models to predict compound activity and properties, thus aiding in the identification of compounds with ideal characteristics and efficacy. Overall, the article provides an in-depth examination of various computational strategies for F2L optimization, offering both theoretical insights and practical guidance for the development of F2L compounds in drug discovery.

Applications

Through the examination of the relationship between a compound's structure and its biological activity, SAR optimization enables the identification of pivotal chemical groups or structural features that enhance efficacy, leading to the design of more potent drug candidates.
SAR optimization also plays a crucial role in increasing the selectivity of glycans towards specific targets, thereby minimizing interactions with non-target proteins and reducing potential side effects.
By refining the chemical structure, SAR optimization can bolster a compound's metabolic stability, thereby prolonging its half-life and ensuring a sustained effective concentration within the body.
SAR optimization can be used for enhancing the pharmacokinetic properties of compounds, improving their ADME profiles, and making them more suitable for oral or alternative routes of administration.

Advantages

We possess an extensive DEGL which offers a vast array of glycan compounds. This expansive selection facilitates the identification of candidate compounds with high affinity for the target.
During hit optimization, we employ sophisticated chemical modification strategies. These techniques introduce new functional groups to enhance pharmacological properties, including efficacy, selectivity, and safety.
Our researchers utilize advanced computational tools to boost the efficiency of SAR optimization.

Frequently Asked Questions

How do we perform initial compound screening?
- Initiate the process by pinpointing the specific target that the screening will address. This foundational step shapes the overall screening strategy and the criteria for choosing the glycan library.
- Construct a DEGL that may include both established glycans and those that are newly synthesized. It is crucial to ensure that the library possesses a wide-ranging diversity to optimize the effectiveness of the screening process.
- Select a suitable screening strategy, tailored to the characteristics of the target and the requirements of the screening initiative.
- Conduct the screening process and evaluate the data to identify potential hits.
What scale is the DEGL library we have built?
- We customize and construct the DEGL library based on our clients' specific requirements. We are capable of synthesizing libraries at the scale of millions if needed.

In the stage of SAR Optimization, CD BioGlyco specializes in the meticulous enhancement of hit compounds uncovered during initial screening. This comprehensive service encompasses the detailed analysis of these preliminary hits, executing SAR studies to delineate how variations in molecular structure influence biological activity and the subsequent design and synthesis of novel analogs. If you want to optimize hits, contact us!

Reference

de Souza Neto, L.R.; et al. In silico strategies to support fragment-to-lead optimization in drug discovery. Frontiers in chemistry. 2020, 8: 93.

For research use only. Not intended for any clinical use.