Recently fragment-based drug discovery (FBDD) has emerged as a more promising and focused approach which is resulting in the quality, rather than the quantity, of hits and leads. The principles of this strategy are different from those of classical HTS.
The starting point of this approach is always a small chemical entity, a fragment, with potential low affinity for the selected target. Because of their small size, they occupy a smaller region of chemical space if compared with conventional HTS compounds; hence, fragment libraries may provide a good diversity with a relatively low number of compounds. It has been suggested that about 100,000 of fragments are commercially available, but in reality this is an illusion. The low drug-like properties of 100,000 are the main severe restrictions. The most of these fragments are reactive (Michael acceptors, alkylating/arylating, redox agents, etc.) or insoluble in water compounds. There are also a lot of singletons as well as a huge series of very similar compounds (e.g. arylpiperazines).
ChemDiv propose the rational selection and design of drug-like scaffolds and synthesis around them small series (5-10 molecules) of lead-like fragments. The main principle of scaffold selection consists in the use of knowledge database of known GPCRs or ion-channel ligands and enzyme effectors as the prototypes. The single lead compound may be a source for the generation of several fragments series. The compounds chosen for synthesis should possess lead-like properties related to the next rules: number of non-H atoms 20; MW 300; ClogP 3.0; PSA 80; 1 HBA 5; HBD 3; number of RB 3; number of ring > 0; etc. The fragments selected should contain only C, H, N, O, S, P, F, Cl, and Br atoms. The drug-like properties of fragments are guaranteed by applying the special medicinal chemistry filters. The fragments selected should possess a good water solubility (Clog SW > -3.0) that requires for HCS. In total fragments should satisfy key features such as diversity, reduced structural complexity, drug-/lead likeness and possess a great potential for “fragment evolution” and “fragment linking”.
Fragment Based (Library: Rule of 3):
Ro3: Guidance in assessing lead-like character (MW 300 ;ClogP 3;HBD 3;HBA 3;RTB 3;PSA 60 2) Additional criteria's: (1 HBA 3; Solubility in water logSW > -3; Solubility in DMSO) The overwhelming majority of fragments are Ro-3 compliant. For several chemotypes MW allows to be <330 (or ClogP <5; or HBA <5; or RTB <6). Only one point of Ro-3 can be violated!
Non-peptide Peptidomimetic Library
Arg, Pro, Glu, Asp; beta-, gamma-turns; dipeptide- and tripeptide mimic including RGD, AVPI and PDZ motifs, beta sheet, SH2 mimics.
The main set of rules / selection criteria used for design and selection of this library: the usage of physico-chemical parameters was not considered as the prevailing rule; with the only guidance of MW -4 (important for compounds solubility).
The primary rule for such design & selection is the search for structural motifs typical for non-peptide peptidomimetics (available literature search, Integrity, SciFinder, and Beilstein data bases); specifically were considered:
• molecules with beta- and gamma-turns • molecules with conformational constrained amino acids • molecules based on non-natural amino acids that can be considered as bioisosteric • analogs of natural amino acids • molecules containing non-typically substituted natural amino acids (e.g.: with CF3, CN, etc.) • natural non-proteinogenic amino acids were also considered as a starting point for follow • up design and/or selection • privileged structures were also considered as basis for follow up design and/or selection • dipeptide-like moieties were considered as well • compounds with cis-configuration of amide bond were considered as well • where possible 3D-docking and pharmacophore search were also deployed to hop the corresponding molecules.