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Combinatorial Library


Compared to traditional synthetic chemistry, combinatorial chemistry synthetic methods allow a very large number of molecules to be synthesised much more rapidly and at lower cost. Combinatorial chemistry libraries are commonly represented by one or more structures with a small number of R-group positions. And there are lists of alternative groups for each R-group position. Peptides and oligonucleotides are firstly synthesized using combinatorial library approaches. Since then, proteins, synthetic oligomers, small molecules, and oligosaccharides are produce successfully with this powerful tool. In general, the method applied for library preparation depends on the type of library desired. All combinatorial library methods include the following three main steps: library preparation, library components screening, and chemical structures of active compounds determination. The goal of chemical compound library design is to reduce the number of molecules as well as maintain the diversity of the library. Combinatorial library therefore has the potential of finding leads more rapidly since only a smaller number of molecules are required to be tested by avoiding molecules which are very similar.

Application of Combinatorial Library

  • Virtual screening with molecular docking
  • Virtual screening using pharmacophore technology
  • Virtual screening using molecular shape and electrostatic technology
  • Use QSAR model or other models to predict the activity of compounds

Combinatorial chemistry scheme for compound library development.Figure 1. Combinatorial chemistry scheme for compound library development. (Feroz, K.; et al. 2011)

Combinatorial Library Design Process

At Alfa Chemistry, we synthesize a compound library by drawing a reaction route, enumerate the reactants through chemoinformatics technology, and use multiple molecular fingerprint to allow various reagents and intermediates to 'react' and finally obtain a virtual product library, which is also called combinatorial library.

1) Read into the reagent compound database.
2) Use SMARTS language to identify the reactants in the reagent database, and calculate the number of groups for each compound.
3) Use SMARTS language to establish reaction and product.
4) Calculation and filtration of the physical and chemical properties of the product.
5) Save the product in sdf format.

Our Services

At Alfa Chemistry, we mainly support common combinatorial library construction and centralized combinatorial library design.

  • Common combinatorial library construction

We use combinatorial library enumerator to build medium-scale combinatorial library, which supports symmetric substitution, peptide substitution, double hook connection, loop generation and chirality.

  • Centralized combinatorial library design

At Alfa Chemistry, the product-based method is applied to design the centralized library, and the reactants are sorted according to the probability of being part of the active compound. The sorting principle is developed based on linear or binary QSAR, fingerprint, pharmacophore, fingerprint or comprehensive model. We use Monte Carlo technology to avoid enumeration traversal, which is suitable for effectively sorting reactants in the design of very large virtual libraries.

Combinatorial Library Method

1. Fragment screening

  • Molecular scaffold
  • R-group

2. Fragment enumeration

  • Screening attachment point A0 on A1->A4
  • Combinatorial molecules


  • RECAP analysis: Generate fragments from source molecules
  • Extend SMILES

4. RECAP synthesis

  • Reconstruct molecules by fragments from RECAP analysis: Atom environment, reaction rules, attachment points and databases from RECAP analysis

5. Breed

  • Crossover by Genetic algorithm
  • Ligand-based design and structure-based design
  • Crossover points defined by all superimposed bond pairs

Alfa Chemistry's Advantages

  • High Diversity Precision

We can incorporate multiple variant domains into one or multiple scaffolds and have precise control over codon usage, amino acid distribution, and length variation.

  • Verified Quality

Our method is under rigorous quality control including NGS verification of modified regions. We provide sequence variant ratios documented and uniform distribution of user-defined variants. Moreover, there is no premature stop codons or unwanted codons.

  • Flexibility

Our scientists can design all sequences, single or multiple domains and combinations. Our mature modular synthesis system enables iteration of future libraries.

Our combinatorial library 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!


  • Feroz, K.; et al. Modern Methods & Web Resources in Drug Design & Discovery. Letters in Drug Design & Discovery. 2011, 8: 469-490.

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