P-loop flexibility

ASINEX has elaborated a library of diverse macrocycles using an effective tool box of synthetic methods. The resulting scaffolds are novel, tremendously diverse, medchem-relevant, macrocyclic frameworks.

Macrocyles tend to be larger than traditional screening molecules which make them perfect discovery tools for targets with shallow or extended binding sites. At the same time, their unique character based on restricted flexibility and ability to form intra-molecular hydrogen bonds allows for design approaches effectively optimizing properties such asaqueous solubility and membrane permeability. Many of these macrocycles have been tested for aqueous and DMSO solubility with cut-offs applied at 10 mM in DMSO and 50 µM in PBS (pH 7.4) followed by PAMPA permeability assay.

Cyclic peptides are polypeptide chains taking cyclic ring structure, which exhibit diverse biological activities, such as antibacterial activity, immunosuppressive activity and anti-tumor activity. Cyclic peptides, with the features of good binding affinity, target selectivity and low toxicity, show great success as therapeutics. Multiple cyclic peptides are currently in clinical use, for examples, gramicidin and tyrocidine with bactericidal activity, cyclosporin A with immunosuppressive activity, and vancomycin with antibacterial activity. Furthermore, cyclic peptides usually have the sufficient size and a balanced conformational flexibility/rigidity for binding to flat protein-protein interaction (PPI) interfaces, which have potential to develop PPI drugs.

MCE offers a unique collection of 100 cyclic peptides, all of which have good bioactivities. MCE Cyclic Peptide Library is a powerful tool for drug discovery and PPI inhibitor screening.

Unlike highly conserved orthosteric sites, allosteric sites exhibit low conservation, high hydrophobicity, weak polarity, confined geometry, and dynamic cryptic properties. Rather than rigid keyhole-like cavities, they typically appear as flexible grooves, subunit interface clefts, or shallow depressions formed by protein conformational changes.

Based on the dynamic, hydrophobic, and elongated nature of allosteric pockets, MCE has carried out targeted fragment modification and screening under strict physicochemical criteria: MW 120–280 Da, HBD ≤ 2, HBA ≤ 3, PSA 30–80 Ų, rotatable bonds ≤ 2, cLogP 1–3.5. High 3D diversity was further ensured by PMI analysis, yielding fragments with excellent shape complementarity to allosteric pockets.

This library contains 1,800 structurally diverse, drug-like fragments, this library supports allosteric drug development and pocket optimization. It significantly improves screening hit rates and enables efficient, precise early-stage R&D of allosteric drugs.

Linkers, as key structural units in PROTAC molecules that connect the two functional ends, not only determine the overall molecular conformation and spatial compatibility but also directly influence the stability of the ternary complex, as well as cellular permeability and degradation efficiency. In recent years, with the widespread application of click chemistry in medicinal chemistry, the incorporation of bioorthogonal reactive groups such as azides (-N₃) into PROTAC linker design has become an emerging research focus, providing an important tool for modular assembly and rapid structural optimization.

The MCE Azide PROTAC Linker Library contains 0 linkers specifically designed for targeted protein degradation molecule design and optimization. These linkers serve as efficient “click handles,” enabling rapid and highly selective covalent coupling with alkyne reaction partners, thereby facilitating modular assembly and structural diversification of PROTAC molecules. In drug development, this design not only improves the efficiency of molecular construction but also significantly accelerates the screening and optimization of lead compounds. Meanwhile, by tuning linker properties such as length, flexibility, and polarity, the ability to form ternary complexes and degradation activity can be optimized.

In PROTAC drug development, linkers are often one of the key variables determining drug-likeness and degradation efficiency. Since PROTAC systems must simultaneously satisfy target protein binding, E3 ligase recruitment, and intracellular spatial conformational matching, their structural design is essentially a multi-parameter optimization problem. Differences in linker rigidity, flexibility, and spatial extension can significantly influence the formation pathway and stability of the ternary complex, leading to substantial variations in degradation activity. Therefore, the development of linker systems with modular tunability and high structural expandability has become an important direction in PROTAC optimization.

The MCE Alkyne PROTAC Linker Library contains 0 linkers based on terminal and internal alkyne scaffolds, forming a highly derivatizable linker module system. These linkers serve as standardized building blocks for rapid assembly and iterative optimization of PROTAC molecules, and support efficient conjugation with azide-containing functional groups via click chemistry. In practical drug development, this type of structure not only facilitates the construction of diverse linker space libraries, accelerating lead compound screening, but also enables systematic tuning of molecular geometry and physicochemical properties, thereby improving ternary complex stability and targeted protein degradation efficiency.

Seven-membered rings are privileged medium-sized scaffolds with distinct twist-chair conformations and greater 3D diversity than five- and six-membered rings. Their flexible conformations allow induced-fit protein binding and precise pharmacophore positioning. They also modulate Fsp³, pKa and logP to enhance solubility and permeability. Azepanes, oxepanes and benzodiazepines serve as bioisosteres for hit discovery against GPCRs, ion channels and kinases.

Widely found in plant and microbial alkaloids, seven-membered heterocycles show excellent biocompatibility and target affinity. They underpin many approved drugs for CNS, cancer and infectious diseases, including diazepam, imipramine and carbamazepine. Clinical candidates further highlight their unique value. However, high transannular strain and synthetic difficulty limit their availability, leaving them rare in standard screening libraries.

MCE 7 Membered Scaffold Library contains 2,792 structurally diverse, lead-like molecules covering azepanes, oxepanes, benzodiazepines and dibenzazepines. With varied substitutions, chiral centers and synthetic accessibility, it fills the shortage of medium-ring scaffolds. Ideal for HTS, virtual screening and SAR studies, these novel, patent-clear compounds offer a distinctive starting point for drug discovery in CNS disorders, oncology, antivirals and challenging targets such as PPIs.