p-site

2',5'-Dideoxyadenosine is a potent and non-competitive adenylyl cyclase inhibitor, binding to the P-site with an IC50 of 3 μM.

Sigma-LIGAND-1 is a selective Sigma Receptor ligand with IC50 values of 16 nM and 19 nM at the DTG site and the PPP site, respectively, and a Ki of 4000 nM at the dopamine D2 receptor.

OGG1-IN-08 (OGG1-IN-O8) is an inhibitor of 8-oxoguanine DNA glycosylase 1 (OGG1;IC50 : 0.35 μM)

INCA-6 (Triptycene-1,4-quinone) is a cell-permeable NFAT inhibitor that disrupts CN-NFAT signaling by targeting the NFAT(P) substrate at the calcineurin (CN) phosphatase site.

ML318 is a biaryl nitrile PvdQ acylase inhibitor (IC50 of 20 nM for binding in the acyl-binding site). ML318 inhibits P. aeruginosa (PAO1) with IC50 of 19 μM. ML318 prevents pyoverdine production and limits the growth of P. aeruginosa under iron-limiting

BACE1-IN-5 (Compound 15), a potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, demonstrates significant efficacy with an IC50 of 9.1 nM for BACE1 inhibition and an impressive IC50 of 0.82 nM against cellular amyloid-β (Aβ) production. Additionally, it is engineered to enhance hERG inhibition and P-gp efflux, indicating its optimized medicinal chemistry profile [1].

BIIE-0246 is a selective NPY2R antagonist with an IC50 of 15 nM at the rat [125I]PYY3-36 site. It reduces NPY-stimulated expression of p-AKT S473 and P-p44/42 MAPK.

MMV390048 is an antimalarial agent and is a representative of a new chemical class of Plasmodium PI4K inhibitor (Kdapp=0.3 μM). MMV390048 binds to the ATP binding site of Plasmodium PI4K and does not bind to other P. falciparum and human kinases apart from human PIP4K2C, thus alleviating potential kinase-mediated safety concerns.

GSK-3β inhibitor24 (Compound 41) is a potent GSK-3β inhibitor with an IC50 of 0.22 nM. It increases GSK-3β phosphorylation at the Ser9 site in a dose-dependent manner and inhibits tau protein hyperphosphorylation by reducing the abundance of p-tau-Ser396. The compound upregulates β-catenin and neurogenesis-related markers (GAP43 and MAP-2), demonstrating significant anti-Alzheimer's disease (AD) activity.

Antitumor agent-200 (Compound 2g) is a microtubule synthesis inhibitor that binds to the colchicine site on tubulin, causing G2/M cell cycle arrest and inducing reactive oxygen species (ROS) production. It demonstrates significant inhibitory activity against P-glycoprotein (P-gp) overexpressing cell lines MCF7/ADR and KBV200, with resistance indices (DRI) of 0.83 and 0.58, respectively. In an MCF-7 xenograft model, Antitumor agent-200 (at 25 mg/kg, administered intraperitoneally) achieves a 57.2% tumor growth inhibition rate. This compound is applicable for research in the field of cancer therapy.

GPV0057 (Compound 5d) is a potent and selective inhibitor of P-glycoprotein (P-gp). It also acts as a selective activator of the potassium channel Kir2.1. By competitively binding at the substrate binding site of P-gp, GPV0057 inhibits ATP-dependent drug efflux, thereby reversing multidrug resistance in tumor cells. Additionally, it stabilizes the open state of Kir2.1, enhancing potassium ion influx. GPV0057 has potential applications in the study of tumors with high P-gp expression and Kir2.1-related diseases, such as heart failure and Andersen-Tawil syndrome.

ELQ-121 is a potent inhibitor of the ubiquinol oxidation (QO) site in parasites. It exhibits an in vitro IC50 of 0.05 nM against both chloroquine-sensitive and multi-drug resistant Plasmodium falciparum. ELQ-121 also inhibits Toxoplasma gondii and Neospora caninum with an in vitro IC50 of less than 1 nM. It hinders the proliferation of Bacteroides fragilis tachyzoites with an IC50 of 0.49 nM and induces mitochondrial disruption. Furthermore, ELQ-121 can be formulated into a polyethylene glycol carbonate prodrug, which shows efficacy against P. yoelii in mice. ELQ-121 is applicable for antimalarial research.

GABA receptor antagonist 2 (Compound IId) is a GABA receptor blocker with an LC50 of 0.0735 μg/mL against Plutella xylostella (P. xylostella). This compound exhibits significant insecticidal activity against P. xylostella and its resistant strains, as well as against Spodoptera frugiperda and Chilo suppressalis. GABA receptor antagonist 2 can bind to the GABA receptor at the Drosophila RdlG335 site and is useful for managing resistant pest populations.

IAP ligand 9 is a SMAC mimetic and binds to the IAP (inhibitor of apoptosis protein) BIR domains, selectively targeting cIAP1-BIR3 and XIAP-BIR3, while showing minimal affinity for XIAP-BIR2, with SPR pKD values of 7.0, 8.0, and 5.0, respectively. As an IAP ligand module, it can be conjugated via linkers with degraders targeting the TEAD1 P site to form IAP-recruiting proteolysis-targeting chimeras (PROTACs/IPDs). This IPD recruits the IAPE3 ubiquitin ligase to form the TEAD1-IPD-IAP ternary complex, mediating ubiquitination and proteasome-dependent degradation of TEAD1 and inducing autodegradation of cIAP1. IAP ligand 9 and related degraders are useful in the study of solid tumors such as malignant pleural mesothelioma associated with abnormal activation of the Hippo pathway.

CHNQD-01522 is a microtubule inhibitor that targets the colchicine binding site on β-tubulin. It disrupts microtubule polymerization and can evade P-glycoprotein transport in cancer cells. This compound inhibits cancer cell proliferation, prevents tumor cell colony formation, arrests the cell cycle at the G2/M phase, and induces apoptosis. CHNQD-01522 upregulates Bax and activates caspase-9 and caspase-3. In xenograft models of subcutaneous and orthotopic liver cancer, it exhibits antitumor activity and is applicable for hepatocellular carcinoma research.

Capreomycin IA is a bactericidal agent that targets bacterial ribosomes, with its antibacterial activity primarily limited to mycobacteria. It inhibits protein synthesis by blocking the translocation of peptidyl-tRNA from the A-site to the P-site. Capreomycin IA is active against Mycobacterium tuberculosis and is utilized in research related to tuberculosis.

ZW-49 is a pan-EGFR inhibitor with oral bioavailability, showing IC50 values ranging from 0.03 to 1.5 nM. It effectively inhibits all EGFR mutant subtypes and demonstrates selectivity for wild-type EGFR and other target families. ZW-49 blocks the ATP binding site and occupies a conserved hydrophobic sub-pocket, preventing steric clashes with P-loop mutations (PACC). It suppresses cancer cell proliferation, induces G0/G1 cell cycle arrest and apoptosis, and exhibits antiproliferative activity in xenograft mouse models. ZW-49 is applicable in cancer research, including studies on non-small cell lung cancer.

NFI23 is a GluN2B-NMDAR inhibitor with an IC50 of 1.31 μM and a Ki of 5.98 nM. It can cross the blood-brain barrier and binds to the ifenprodil binding site of GluN2B-NMDAR, reducing NMDA-induced Ca2+ influx and reactive oxygen species (ROS) production. It helps maintain mitochondrial membrane potential, inhibits neuronal apoptosis, and restores p-ERK1/2 expression. NFI23 demonstrates neuroprotective effects against NMDA-induced cytotoxicity and in a rat model of middle cerebral artery occlusion (MCAO), making it useful for ischemic stroke research.

Eritadenine (Lentinacin) is a mushroom-derived compound that acts on the adenosine P-site in adipocyte plasma membranes, lowering cholesterol levels and altering phospholipid composition in rat models of hyperhomocysteinemia, used in anxiety disorder studies.

FSBA hydrochloride inhibits covalently anthrax edema factor.

CAY10761 is an inhibitor of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1; IC50s = 467 and 429 μM for the human and snake venom enzymes, respectively).1,2 It also inhibits mushroom tyrosinase (Ki = 1.9 μM) and urease from jack bean, P. mirabilis, and B. pasteurii (IC50s = 0.093, <0.125, and 0.089 mM, respectively, at pH 8.2).3,4 |1. Khan, K.M., Fatima, N., Rasheed, M., et al. 1,3,4-Oxadiazole-2(3H)-thione and its analogues: A new class of non-competitive nucleotide pyrophosphatases/phosphodiesterases 1 inhibitors. Bioorg. Med. Chem. 17(22), 7816-7822 (2009).|2. Onyedibe, K.I., Wang, M., and Sintim, H.O. ENPP1, an old enzyme with new functions, and small molecule inhibitors - A STING in the tale of ENPP1. Molecules 24(22), E4192 (2019).|3. Ghani, U., and Ullah, N. New potent inhibitors of tyrosinase: Novel clues to binding of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides to the dicopper active site. Bioorg. Med. Chem. 18(11), 4042-4048 (2010).|4. Amtul, Z., Rasheed, M., Choudhary, M.I., et al. Kinetics of novel competitive inhibitors of urease enzymes by a focused library of oxadiazoles/thiadiazoles and triazoles. Biochem. Biophys. Res. Commun. 319(3), 1053-1063 (2004).

DBCO-PEG4-VC-PAB-MMAE is a drug-linker complex consisting of an ADC linker (DBCO-PEG4-VC-PAB) and the tubulin polymerization inhibitor MMAE. It is a key building block utilized for the synthesis of antibody-drug conjugates (ADCs). MMAE, a synthetic derivative of dolastatin 10, functions as a potent mitotic inhibitor by blocking tubulin polymerization. The reagent features a DBCO group, enabling strain-promoted alkyne-azide cycloaddition (SPAAC) with azide-containing molecules via click chemistry. The VC-PAB (Valine-Citrulline-p-aminobenzylcarbamate) moiety is a Cathepsin B-cleavable linker, ensuring site-specific drug release within the lysosomal environment of target cells.

INDOPY-1 is a Nucleotide-Competing Reverse Transcriptase Inhibitor. INDOPY-1 was the first NcRTI discovered, displaying reversible competitive inhibition of dNTP binding. 3,4 Biochemical studies showed that INDOPY-1 arrests RT/DNA in a post-translocated (P site) complex.

OP-145, a derivative of the antimicrobial peptide LL-37, is a synthetic antimicrobial peptide showing activity against E. coli, P. aeruginosa, C. albicans, and A. niger, with minimum inhibitory concentrations (MICs) of 2, 3, 6, and 18 µM, respectively. Utilizing poly(lactic-co-glycolic acid) (PLGA) microspheres loaded with OP-145 effectively prevents biofilm formation in a mouse model of bone infection, which is initiated by surgical femoral fracture and subsequent bacterial inoculation at the fracture site.