Target-oriented Design

In target-based screening, scientific staffs are committed to investigating the design of target-focused libraries, such as screening collections of compounds specifically tailored to modulate a given target or target family. The aim of designing such library designs is to improve hit rates. Currently, scientists have developed and successfully applied a variety of methods for designing such target-focused libraries depending on the amount of structural and ligand information available for a target (or family) of interest. For example, if the crystal structure of the target is available, a docking algorithm can be used to select compounds with good electrostatic complementarity and shape to bind to the protein pocket. And this strategy is widely used for kinase. If a large number of known active ligands can be retrieved, ligand-based design methods utilizing molecular fingerprinting or pharmacophore modeling can be used for the design of GPCR and ligand-gated ion channel library. For target families such as GPCR, complex computer algorithms are useful to redesign known ligands to show the desired activity. In general, target-focused libraries cover only limited structural diversity and are based on few core scaffolds that are differently substituted at multiple points.

Figure 1. A one-bead one-compound (OBOC) library of thousands of unique peptoid compounds bound to TentaGel beads. (Yazdani, U. et al. 2016)

Library Design Methods

• Druglikeness scoring functions

The scoring function plays a crucial role in focused library design. BOC Sciences creates a genetic algorithm (GA) to sample a small subset of the total combinatorial space to quickly identify high-scoring molecules. Our team also uses structural diversity and binding affinity scores in combination with our newly improved drug similarity scoring function to generate target-focused libraries. Finally, our well-designed libraries have the unique advantages of high hit rates, novel structures, and good ADME/T. In addition, our libraries not only reproduces key fragments in the approved drugs, but also generate some novel structures with higher activity than published ligands.

• Pharmacophore modeling

BOC Sciences supports the application of three-dimensional (3D) pharmacophore fingerprinting in combinatorial library design. In a structure-design based on multiple pharmacophore approach, we use the shape of the target site as an additional constraint, thereby optimizing product diversity and unique 4-point pharmacophores in chemical space. As a result, we are able to quantify the number and identity of the pharmacophoric hypotheses that can be matched by a compound or a library of compounds during the docking process.

• 3D conformation

Generating accurate 3D structures for small compounds is no a small challenge, and several methods have been developed using either rule-based methods (essentially structure data-based methods) or data-based methods. We have applied an optimized program that provides fast, automated and reliable access to 3D conformation generation for small molecules. In this software, we use distance geometry to generate 3D conformations of small molecules, and optimize the in silico screening by automated molecular mechanics, which helps to prepare compound collections prior to high-throughput virtual screening computations.

BOC Sciences provides professional, rapid and high-quality services of Target-oriented Design design at competitive prices for global customers. Personalized and customized services of Target-Oriented Design design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!