inhibition screening

Nucleoside and nucleotide analogues are synthetic, chemically modified compounds that have been developed to mimic their physiological counterparts in order to exploit cellular metabolism and subsequently be incorporated into DNA and RNA to inhibit cellular division and viral replication. In addition to their incorporation into nucleic acids, nucleoside and nucleotide analogues can interact with and inhibit essential enzymes such as human and viral polymerases (that is, DNA-dependent DNA polymerases, RNA-dependent DNA polymerases or RNA-dependent RNA polymerases), kinases, ribonucleotide reductase, DNA methyltransferases, purine and pyrimidine nucleoside phosphorylase and thymidylate synthase. These actions of nucleoside and nucleotide analogues have potential therapeutic benefits — for example, in the inhibition of cancer cell growth, the inhibition of viral replication as well as other indications.

MCE offers a unique collection of 562 nucleotide compounds including nucleotide, nucleoside and their structural analogues. MCE Nucleotide Compound Library is a useful tool to discover anti-cancer and antiviral drugs for high throughput screening (HTS) and high content screening (HCS).

A diverse compound library with favorable ADMET properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity) is crucial in drug discovery. Early evaluation of ADMET properties allows for the exclusion of molecules with unfavorable profiles at the initial stages, thereby reducing the risk of late-stage development failures, lowering R&D costs, and accelerating optimization of lead compounds. Based on predictions from ADMET-related AI algorithms, the compounds in this library are predicted to exhibit favorable oral bioavailability (F > 30%), reasonable plasma protein binding (PPB < 98%), minimized CYP3A4 inhibition potential (inhibition probability < 50%, CYP3A4 is the most critical drug-metabolizing enzyme in the cytochrome P450 family) , low toxicity profiles, with 140 potentially toxic substructures pre-identified and excluded via substructure searching to eliminate compounds containing hazardous fragments. The diversity library enables broad applicability in high-throughput screening (HTS) and high-content screening (HCS).

Ion channels are key proteins on the cell membrane that regulate the flow of ions across membranes. They participate in nearly all physiological processes, including nerve conduction, muscle contraction, heart rhythm, and pain perception. Abnormalities in their function can lead to various serious diseases such as arrhythmia, epilepsy, hypertension, neuropathic pain, and cancer. Therefore, ion channels are highly valuable drug targets—over 15% of approved drugs target ion channels currently, demonstrating their irreplaceable therapeutic value in cardiovascular, neurological, and analgesic fields.

MCE has collected a library of over 5,000 reported ion channel-related bioactive compounds targeting major sites such as Na+ channels, K+ channels, Ca2+ channels, GABA receptors, iGluRs, and others. Using AI models, these compounds are characterized through both 2D representations (molecular fingerprints, pharmacophores) and 3D representations (3D conformation) to screen for a collection of lead-like compounds highly similar to known active molecules. Additionally, an hERG channel prediction algorithm integrating XGB and ISE mapping strategy is employed to assess and exclude potential cardiotoxicity in the library.. This step significantly reduces safety risks in subsequent screenings, particularly for ion channel drug development related to cardiovascular systems (e.g., Nav1.5, Cav1.2), effectively minimizing failures due to hERG inhibition and serving as a valuable tool for ion channel drug screening.

Small molecule covalent inhibitors, or irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity, such that covalent warheads can target rare residues of a particular target protein, thus leading to the development of highly selective inhibitors and achieving a more complete and continued target occupancy in living systems. In recent years, the distinct strengths of covalent inhibitors in overcoming drug resistance had been recognized. However, toxicity can be a real challenge related to this class of therapeutics due to their potential for off-target reactivity and has led to these drugs being disfavored as a drug class. The drug design and optimization of covalent inhibitors has become a hot spot in drug discovery.

MCE covalent inhibitor library contains 5,794 small molecules including identified covalent inhibitors and other molecules having common covalent reactive groups as warheads, such as acrylamides, activated terminal acetylenes, sulfonyl fluorides/esters, cloracetamides, alkyl halides, epoxides, aziridines, disulfides, etc.

MCE Covalent inhibitor Library plus, with more powerful screening capability, further complement Covalent inhibitor Library (HY-L036) by adding some fragment compounds with covalent warheads.

Small molecule covalent inhibitors, or irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity, such that covalent warheads can target rare residues of a particular target protein, thus leading to the development of highly selective inhibitors and achieving a more complete and continued target occupancy in living systems. In recent years, the distinct strengths of covalent inhibitors in overcoming drug resistance had been recognized. However, toxicity can be a real challenge related to this class of therapeutics due to their potential for off-target reactivity and has led to these drugs being disfavored as a drug class. The drug design and optimization of covalent inhibitors has become a hot spot in drug discovery.

MCE covalent inhibitor library contains 1,430 small molecules including identified covalent inhibitors and other bioactive molecules having common covalent reactive groups as warheads, such as acrylamides, activated terminal acetylenes, Sulfonyl fluorides/esters, cloracetamides, alkyl halides, epoxides, aziridines, disulfides, etc.

Small molecule covalent inhibitors, or irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity, such that covalent warheads can target rare residues of a particular target protein, thus leading to the development of highly selective inhibitors and achieving a more complete and continued target occupancy in living systems. In recent years, the distinct strengths of covalent inhibitors in overcoming drug resistance had been recognized. However, toxicity can be a real challenge related to this class of therapeutics due to their potential for off-target reactivity and has led to these drugs being disfavored as a drug class. The drug design and optimization of covalent inhibitors has become a hot spot in drug discovery.

MCE Lead-like Covalent Screening Library offers a valuable resource of 1,049 lead-like compounds with commonly used covalent warheads. These warheads, such as acrylamide, activated terminal alkyne, acyloxymethyl ketone, and boronic acid, are capable of reacting with specific amino acid residues, including cysteine, lysine, serine, and histidine. The inclusion of these reactive warheads in the library allows researchers to explore the potential of covalent inhibition, a powerful approach in drug discovery.