Topological diversity is a well-known prerequisite for success in the search for drug leads with biological activity.

Other chemistry-based drug discovery companies concentrate on straightforward chemical transformations, leading to large libraries, which appear attractive, but have a low-to-moderate diversity in structures. The library approach is inefficient and very expensive if carried out at large pharmaceutical company HTS facilities, because the libraries are redundant. An impressive number of compounds indicates nothing about the true diversity of the structures contained in the library.  In contrast, Tranzyme’s HitCREATE™ library provides extensive chemical and conformational diversity in a limited number of compounds.
 

In lead optimization, Tranzyme’s combinatorial chemistry methods focus on the rapid preparation of highly diverse structures in a single synthesis session, enabling efficient routes for optimizing any activity that is observed.

Often, hits generated from conventional high-throughput screening require significant additional efforts in chemistry development, and structural modification in order to generate lead candidates for further advancement.  With the HitCREATE™ library, however, robust and versatile synthetic methods are already established, providing immediate access to additional compounds for hit-to-lead optimization.  Tranzyme’s combinatorial chemistry methods also permit the rapid improvement of desired activity simultaneously with modification of other pharmacological properties.

HitCREATE™ has been designed to be a knowledge-based or “smarter” library, in order to access more complex structures that would be of greater interest from a pharmaceutical drug discovery perspective.

Drug-Like Properties of Tranzyme’s HitCREATE™ Library

Tranzyme’s HitCREATE™ library contains distinct macrocyclic small molecule compounds ranging from 15- to 19-atom ring size.  Their molecular weights are in an optimal range for pharmaceutical development. The design of the HitCREATE™ library is not only based on optimizing diversity in terms of chemical composition and spatial orientation — it is also based on appropriate physicochemical properties (Lipinski Rules of Five). The table below shows the overall calculated parameters of drug-likeness for the HitCREATE™ library compared to generally accepted values.

Tranzyme Pharma offers two strategies in library design for its chemistry-based drug discovery partnerships:

• A broad approach, in which lead molecules can be identified for a given drug target, from a general screening of the HitCREATE™ library.

• A focused approach, in which specific structures can be designed against relevant targets where some structural or activity information is already known. In this case, the information can be gained from initial screening hits, known active peptides and other compounds, target/target-ligand crystal structures or existing structure/activity relationships.