The main content of the fragment-based drug discovery technology is to design and establish a compound library composed of fragment molecules, and then use it to screen out the hit fragment molecules with biological activity. Various physical methods such as X-ray crystallography, nuclear magnetic resonance and mass spectrometry are used to analyze the binding mode and binding strength of these molecular fragments with the target protein. Finally, scientists optimize the structure of the fragment molecules to obtain the lead compound based on the structural information obtained. The use of FBDD has increased in the last decade due to the encouraging results obtained to date in which computational approaches have played an important role to guide and speed up the process. A broad set of computational tools: docking, quantitative structure-activity relationship, fragmentation tools, fragments management tools and fragment-hopping can be utilized in FBDD, providing a clear positive impact.
Figure 1. A workflow of computational FBDD. (Hao, G. F.; et al. 2016)
Advantages of FBDD
FBDD is an important way to identify new lead compounds and has the following advantages:
- Molecular fragments can be sampled more efficiently than larger HTS screening due to their simplicity. Therefore, FBDD is able to perform screening campaigns containing 500-1000 fragments with good selectivity.
- Fragments can bind to their targets more effectively than large molecule due to the small size of the fragments. The ligands hit can provide effective clinical candidates based on structure-oriented optimization. The evaluation of the structure and characteristics of fragments helps to guide optimization.
- In general, the binding affinity of hit fragments is weaker than that of larger hit molecules. Sensitive biophysical techniques such as NMR, surface plasmon resonance, x-ray crystallography, thermal denaturation, isothermal titration calorimetry, etc. can identify ligands with weak affinity and determine hit fragments that interact with allosteric or concealed binding sites.
Our Calculation-based FBDD Process
In order to overcome the limitations of experimental FBDD, the calculation method provides an alternative method to improve the efficiency and success rate of drug discovery. The process of calculating FBDD includes:
- Build a virtual fragment library
- Fragment-based active site map and characterization
- Fragment docking to determine the hit fragment
- Optimization from hit to lead to candidate drug
- Various filters
Physicochemical properties (Rule of Three)
Chemical diversity analysis (Fingerprints)
Synthetic accessibility (RECAP rules)
Solubility prediction (QSAR/QSPR models)
- Pre-filtering of fragment library (Fragement docking)
- Virtual hit identification (Fragement docking)
- Hit expansion
We perform substructure search and similarity search to accelerate hit expansion and obtain structure-activity relationship (SAR) information for secondary design.
- Build fragment hits into novel ligands (De novo drug design)
- Predict binding affinity (Scoring functions)
- Structure-based drug design (Docking and scoring, molecular dynamics)
- Ligand-based drug design (Pharmacophore, QSAR, focused library)
- Fragment docking
We have designed a program for accurate search of discrete three-dimensional space to dock rigid small molecules. The force field-based potential energy function consists of four parts: static electricity between protein-fragments, van der Waals, protein desolvation, and fragment desolvation. Our fragment docking process is as follows:
1. Preparation of protein structure and fragment library
Two different protein structures are prepared for each data set, which fully consider the effect of minor conformational changes in the binding site on virtual screening.
2. Structure optimization
We optimize the tautomeric state of amide (Asn and Gln), hydroxyl (Ser, Thr and Tyr) and thiol (Cys) groups and His residues.
3. Conformations generation and fragments docking
The evaluation of binding energy consists of multiple energy functions based on the force field. The partial charges and VDW parameters of the atoms in the protein and fragments are obtained from the CHARMM36 all-atom force field and the CHARMM general force field, respectively.
- Conformational sampling
Alfa Chemistry supports a conformational sampling tool based on a hybrid genetic algorithm that is able to simulate conformer enumeration or molecules docking. Our unique method can be used in the following application:
1. Specifically dock to a substructure that is covalently anchored to its target.
2. Growing/linking scenarios involving protein site flexibility.
3. Generate the optimized ligand (or close analogs).
4. Good ranking of analogs among decoy compounds (force-field potential energy and RMSD shifts of the original fragment moieties).
5. Accurate predictions of expected binding modes of reference ligands.
- Fragment in silico screening
The core fragment structure is generated from the active molecule using fragment deconstruction analysis and in silico screening by growing fragments to the junction of core fragment structure. We perform an integrated energy calculation to rapidly identify which fragments fit the binding site of a protein. In addition, we construct a simple interface to enable our clients to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration.
Alfa Chemistry's Advantages
- Our high-quality fragment library constructed by computational methods can exclude fragments containing unwanted chemical groups.
- Our well-designed calculation method provides an effective and flexible optimization strategy to improve the activity of hit fragments and drug similarity.
- Our in silico SBDD method can also accumulate or assemble fragments into new molecules with improved potency and drug similarity.
Our fragment-based drug discovery (FBDD) services remarkably reduce the cost, promote further experiments, and accelerate the process of drug design for customers worldwide. Our personalized and all-around services will satisfy your innovative study demands. If you are interested in our services, please don't hesitate to contact us. We are glad to cooperate with you and witness your success!
- Hao, G. F.; et al. ACFIS: a web server for fragment-based drug discovery. Nucleic Acids Research. 2016, W550-W556.