Structure-function relationships in (poly)phenol-enzyme binding: Direct inhibition of human salivary and pancreatic α-amylases.

(Poly)phenols inhibit α-amylase by directly binding to the enzyme and/or by forming starch-polyphenol complexes. Conventional methods using starch as the substrate measure inhibition from both mechanisms, whereas the use of shorter oligosaccharides as substrates exclusively measures the direct interaction of (poly)phenols with the enzyme. In this study, using a chromatography-based method and a short oligosaccharide as the substrate, we investigated the detailed structural prerequisites for the direct inhibition of human salivary and pancreatic α-amylases by over 50 (poly)phenols from the (poly)phenol groups: flavonols, flavones, flavanones, flavan-3-ols, polymethoxyflavones, isoflavones, anthocyanidins and phenolic acids. Despite being structurally very similar (97% sequence homology), human salivary and pancreatic α-amylases were inhibited to different extents by the tested (poly)phenols. The most potent human salivary α-amylase inhibitors were luteolin and pelargonidin, while the methoxylated anthocyanidins, peonidin and petunidin, significantly blocked pancreatic enzyme activity. B-ring methoxylation of anthocyanidins increased inhibition against both human α-amylases while hydroxyl groups at C3 and B3' acted antagonistically in human salivary inhibition. C4 carbonyl reduction, or the positive charge on the flavonoid structure, was the key structural feature for human pancreatic inhibition. B-ring glycosylation did not affect salivary enzyme inhibition, but increased pancreatic enzyme inhibition when compared to its corresponding aglycone. Overall, our findings indicate that the efficacy of interaction with human α-amylase is mainly influenced by the type and placement of functional groups rather than the number of hydroxyl groups and molecular weight.

Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease.

The long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon is the only active autonomously replicating retrotransposon in the human genome. L1 harms the cell by inserting new copies, generating DNA damage, and triggering inflammation. Therefore, L1 inhibition could be used to treat many diseases associated with these processes. Previous research has focused on inhibition of the L1 reverse transcriptase due to the prevalence of well-characterized inhibitors of related viral enzymes. Here we present the L1 endonuclease as another target for reducing L1 activity. We characterize structurally diverse small molecule endonuclease inhibitors using computational, biochemical, and biophysical methods. We also show that these inhibitors reduce L1 retrotransposition, L1-induced DNA damage, and inflammation reinforced by L1 in senescent cells. These inhibitors could be used for further pharmacological development and as tools to better understand the life cycle of this element and its impact on disease processes.

Design, synthesis, and biological evaluation of 5-(1H-indol-5-yl)isoxazole-3-carboxylic acids as novel xanthine oxidase inhibitors.

Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC50 value of 0.13 µM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC50 = 2.93 µM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.

Novel anthraquinone amide derivatives as potential glyoxalase-I inhibitors.

This study aimed to identify novel Glyoxalase-I (Glo-I) inhibitors with potential anticancer properties, focusing on anthraquinone amide-based derivatives. We synthesized a series of these derivatives and conducted in silico docking studies to predict their binding interactions with Glo-I. In vitro assessments were performed to evaluate the anti-Glo-I activity of the synthesized compounds. A comprehensive structure-activity relationship (SAR) analysis identified key features responsible for specific binding affinities of anthraquinone amide-based derivatives to Glo-I. Additionally, a 100 ns molecular dynamics simulation assessed the stability of the most potent compound compared to a co-crystallized ligand. Compound MQ3 demonstrated a remarkable inhibitory effect against Glo-I, with an IC50 concentration of 1.45 µM. The inhibitory potency of MQ3 may be attributed to the catechol ring, amide functional group, and anthraquinone moiety, collectively contributing to a strong binding affinity with Glo-I. Anthraquinone amide-based derivatives exhibit substantial potential as Glo-I inhibitors with prospective anticancer activity. The exceptional inhibitory efficacy of compound MQ3 indicates its potential as an effective anticancer agent. These findings underscore the significance of anthraquinone amide-based derivatives as a novel class of compounds for cancer therapy, supporting further research and advancements in targeting the Glo-I enzyme to combat cancer.

Targeting the cysteine biosynthesis pathway in microorganisms: Mechanism, structure, and drug discovery.

Owing to the global health crisis of resistant pathogenic infections, researchers are emphasizing the importance of novel prevention and control strategies. Existing antimicrobial drugs predominantly target a few pathways, and their widespread use has pervasively increased drug resistance. Therefore, it is imperative to develop new antimicrobial drugs with novel targets and chemical structures. The de novo cysteine biosynthesis pathway, one of the microbial metabolic pathways, plays a crucial role in pathogenicity and drug resistance. This pathway notably differs from that in humans, thereby representing an unexplored target for developing antimicrobial drugs. Herein, we have presented an overview of cysteine biosynthesis pathways and their roles in the pathogenicity of various microorganisms. Additionally, we have investigated the structure and function of enzymes involved in these pathways as well as have discussed drug design strategies and structure-activity relationships of the enzyme inhibitors. This review provides valuable insights for developing novel antimicrobials and offers new avenues to combat drug resistance.

Perspectives and challenges in developing small molecules targeting purine nucleoside phosphorylase.

As a cytosolic enzyme involved in the purine salvage pathway metabolism, purine nucleoside phosphorylase (PNP) plays an important role in a variety of cellular functions but also in immune system, including cell growth, apoptosis and cancer development and progression. Based on its T-cell targeting profile, PNP is a potential target for the treatment of some malignant T-cell proliferative cancers including lymphoma and leukemia, and some specific immunological diseases. Numerous small-molecule PNP inhibitors have been developed so far. However, only Peldesine, Forodesine and Ulodesine have entered clinical trials and exhibited some potential for the treatment of T-cell leukemia and gout. The most recent direction in PNP inhibitor development has been focused on PNP small-molecule inhibitors with better potency, selectivity, and pharmacokinetic property. In this perspective, considering the structure, biological functions, and disease relevance of PNP, we highlight the recent research progress in PNP small-molecule inhibitor development and discuss prospective strategies for designing additional PNP therapeutic agents.

Bioassay-Guided and DeepSAT-Driven Precise Mining of Monoterpenoid Coumarin Derivatives with Antifeedant Effects from the Leaves of Ailanthus altissima.

Demand for the exploration of botanical pesticides continues to increase due to the detrimental effects of synthetic chemicals on human health and the environment and the development of resistance by pests. Under the guidance of a bioactivity-guided approach and HSQC-based DeepSAT, 16 coumarin derivatives were discovered from the leaves of Ailanthus altissima (Mill.) Swingle, including seven undescribed monoterpenoid coumarins, three undescribed monoterpenoid phenylpropanoids, and two new coumarin derivatives. The structure and configurations of these compounds were established and validated via extensive spectroscopic analysis, acetonide analysis, and quantum chemical calculations. Biologically, 5 exhibited significant antifeedant activity toward the Plutella xylostella. Moreover, tyrosinase being closely related to the growth and development of larva, the inhibitory potentials of 5 against tyrosinase was evaluated in vitro and in silico. The bioactivity evaluation results highlight the prospect of 5 as a novel category of botanical insecticide.

Utilizing a structure-based virtual screening approach to discover potential LSD1 inhibitors.

BACKGROUND: Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment. METHODS: In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors. To further validate our findings, we harnessed molecular dynamic simulations and conducted meticulous biochemical experiments to deeply analyze the binding interactions between the protein and compounds. RESULTS: Our results showcased that ZINC10039815 exhibits an exquisite binding mode with LSD1, fitting perfectly into the active pocket and forming robust interactions with multiple critical residues of the protein. CONCLUSIONS: With its significant inhibitory effect on LSD1 activity, ZINC10039815 emerges as a highly promising candidate for the development of novel LSD1 inhibitors.

In Vitro Bioactivities and Characterization of Mycelial Extracts from Different Strains of Phellinus igniarius (Agaricomycetes).

To fully utilize Phellinus igniarius fermentation mycelia, the present study investigated the in vitro antioxidant and α-amylase inhibitory properties of four Ph. igniarius strains. Organic solvents were used to extract fatty acids, phenolics, and flavonoids from the selected mushrooms. The composition and bioactivity of the extracts were evaluated. The lipid yield obtained using petroleum ether (7.1%) was higher than that obtained using 1:1 n-hex-ane+methanol (5.5%) or 2:1 dichloromethane+methanol (3.3%). The composition and relative content of saturated and unsaturated fatty acids in the petroleum ether extract were higher than those in other solvent extracts. Furthermore, ethyl acetate extracts had higher flavonoid and phenolic content and better antioxidant activity than other extracts; however, the 70% ethanol extracts had the best α-amylase inhibitory activity. The supernatant from the ethanol precipitation of aqueous and 1% (NH4)2C2O4 extracts could also be biocompound sources. This comparative study is the first highlighting the in vitro antioxidant and α-amylase inhibitory properties of the four strains of Ph. igniarius extracts prepared using different organic solvents, which makes the investigated species and extracts promising for biological application.

Phytochemical analysis, antioxidant, acetylcholinesterase, and α-amylase inhibitors from extract.

OBJECTIVE: To investigate the effects of Hippeastrum hybridum (HH) as a free radical scavenger, and an inhibitor of the two enzymes i-e Alpha-amylase (α-amylase) and acetylcholinesterase (AChE). METHODS: In this study, HH plant was preliminary analyzed for phytochemical screening and then tested for its antioxidant, anti-α-amylase, and anti-AChE efficiency via standard procedures. RESULTS: Phytochemical analysis shows the existence of different compounds; while Coumarins and quinones were absent. The total phenolic, flavonoid, and tannins content were found to be (78.52 ± 0.69) mg GAE/g, (2.01 ± 0.04) mg RUE/g, and (58.12 ± 0.23) mg TAE/g of plant extract respectively. 28.02% ± 0.02% alkaloid and 2.02% ± 0.05% saponins were present in the HH extract. The HH extract showed the anti-oxidant property with IC50 (50% inhibition) of (151.01 ± 0.13) (HH), (79.01 ± 0.04) (Ascorbic acid) for ferric reducing, (91.48 ± 0.13) (HH), (48.02 ± 0.11) (Ascorbic acid) against Ammonium molybdenum, (156.02 ± 0.31) (HH), (52.38 ± 0.21) (Ascorbic acid) against DPPH, 136.01 ± 0.21 (HH), 52.02± 0.31 (Ascorbic acid) against H2O2, and 154.12 ± 0.03 (HH), (40.05 ± 0.15) (Ascorbic acid) µg/mL against ABTS respectively. Statistical analysis indicated that HH caused a competitive type of inhibition of α-amylase (Vmax remained constant and Km increases from 10.65 to 84.37%) while Glucophage caused the un-competitive type of inhibition i-e both Km and Vmax decreased from 40.49 to 69.15% and 38.86 to 69.61% respectively. The Ki, (inhibition constant); KI, (dissociation constant), Km, (Michaelis-Menten constant), and IC50 were found to be 62, 364, 68.1, and 38.08 ± 0.22 for HH and 12, 101.05, 195, 34.01 ± 0.21 for Glucophage. Similarly, HH causes an anon-competitive type of inhibition of AChE i-e Km remains constant while Vmax decreases from 60.5% to 74.1%. The calculated Ki, KI, Km, and IC50 were found to be 32, 36.2, 0.05, and 18.117 ± 0.018. CONCLUSION: From the current results, it is concluded that HH extract contains bioactive compounds, and could be a good alternative to controlling oxidants, Alzheimer's and Type-II diabetic diseases.

Prenylated indole diketopiperazine alkaloids as phosphatase inhibitors from the marine-derived fungus Talaromyces purpureogenus.

Six previously undescribed prenylated indole diketopiperazine alkaloids, talaromyines A-F (1-6), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data including NMR, HR-ESI-MS, and electronic circular dichroism calculations, together with chemical analysis of hydrolysates. Compounds 1-5 represent the first example of spirocyclic indole diketopiperazines biosynthesized from the condensation of L-tryptophan and L-alanine. Compounds 2 and 4-5 showed selective inhibitory activities against phosphatases TCPTP and MEG2 with IC50 value of 17.9-29.7 µM, respectively. Compounds 4-5 exhibited mild cytotoxic activities against two human cancer cell lines H1975 and HepG-2.

Computational investigation of 2, 4-Di Tert Butyl Phenol as alpha amylase inhibitor isolated from Coccinia grandis (L.) Voigt using molecular docking, and ADMET parameters.

INTRODUCTION: Diabetes Mellitus is the metabolic disorder most prevalent globally, accounting for a substantial morbidity rate. The conventional drugs available for the management of diabetes are either expensive or lack the required efficacy. The purpose of this research is to isolate and characterize an active phytoconstituent from Coccinia grandis and assess its anti-diabetic properties. METHODS AND MATERIALS: Stems of Coccinia grandis are subjected to successive extraction and isolation. The isolated compound by column chromatography was characterized by FTIR (fourier-transform infrared), 1 H NMR (proton nuclear magnetic resonance), and Mass spectroscopy. The antidiabetic potential of the isolated compound was evaluated by in-vitro alpha-amylase inhibitory activity. Further, the compound was subjected to molecular docking studies to study its interaction with the human pancreatic alpha-amylase (Molegro Virtual Docker) as well to determine the pharmacokinetic and toxicity profile using computational techniques (OSIRIS property explorer, Swiss ADME, pkCSM, and PreADMET). RESULTS: The characterization of the compound suggests the structure to be 2,4-ditertiary butyl phenol. The in-vitro alpha-amylase inhibitory study indicated a concentration-dependent inhibition and the IC50 (median lethal dose) value of the isolated compound was found to be 64.36 µg/ml. The docking study with the A chain of receptor 5EMY yielded a favorable docking score of -81.48 Kcal mol-1, suggesting that the compound binds to the receptor with high affinity through electrostatic, hydrophobic, and hydrogen bonds. Furthermore, the silico ADME analysis of the compound revealed improved metabolism, a skin permeability of -3.87 cm/s, gastrointestinal absorption of 95.48 %, and a total clearance of 0.984 log ml min-1 kg-1. In silico toxicity analysis also predicted cutaneous irritations but no carcinogenicity, mutagenicity, or hepatotoxicity. CONCLUSION: The data suggested that the isolated compound (2, 4-tertiary butyl phenol) has the potential to inhibit the alpha-amylase activity and possess optimal ADME properties as well as tolerable side effects.

Classification of buckwheat honey produced in Kazakhstan according to their biochemical ingredients and bioactivities by chemometric approach.

Herein, nineteen buckwheat honey samples collected from 19 stations of different ecological zones of Kazakhstan were analysed for their pollen density, physicochemical properties, chemical composition, antioxidant, anticholinesterase, tyrosinase inhibitory, and urease inhibitory activities with chemometric approaches. Twelve phenolic compounds and fumaric acid were identified using HPLC-DAD, and mainly fumaric, p-hydroxybenzoic, p-coumaric, trans-2-hydroxy cinnamic acids, and chrysin were detected in all samples. The honey samples collected from the Northern zone exhibited best antioxidant activity in lipid peroxidation inhibitory (IC50:8.65 ± 0.50 mg/mL), DPPH• (IC50:17.07 ± 1.49 mg/mL), ABTS•+ (IC50:8.90 ± 0.65 mg/mL), CUPRAC (A0.50:7.51 ± 0.30 mg/mL) and metal chelating assay (IC50:10.39 ± 0.71 mg/mL). In contrast, South-eastern zone samples indicated better acetylcholinesterase (55.57 ± 0.83%), butyrylcholinesterase (49.59 ± 1.09%), tyrosinase (44.40 ± 1.21%), and moderate urease (24.57 ± 0.33%) inhibitory activities at 20 mg/mL. The chemometric classification of nineteen buckwheat honey was performed using PCA and HCA techniques. Both were supported by correlation analysis. Thirteen compounds contributed significantly to the clustering of buckwheat honey based on geographical origin.

Inquiry lipaseoring the mechanism of pancreatic lipase inhibition by isovitexin based on multispectral method and enzyme inhibition assay.

Isovitexin is a main natural flavonoid component in various plants. Currently, the inhibitory effect of isovitexin on pancreatic lipase (PL) and its mechanism have not been elucidated yet. In the present study, we investigated the inhibitory effect of isovitexin on PL, as well as its interaction mechanism, using enzyme inhibition methods, spectroscopic analysis, and molecular simulations. Results showed that isovitexin possessed significant PL inhibitory activity, with IC50 values of 0.26 ± 0.02 mM. The interaction between isovitexin and PL was dominated by static quenching, and mainly through hydrogen bonding and hydrophobic interaction forces. Analysis of fluorescence spectroscopy confirmed that isovitexin binding altered the conformation of the PL. Circular dichroism (CD) spectrum indicated that isovitexin altered the secondary structure of PL by decreasing the α-helix content and increasing the ß-fold content. Molecular simulations further characterize the conformational changes produced by the interaction between isovitexin with PL. The performed study may provide a new insight into the inhibitory mechanism of isovitexin as a novel PL inhibitor.

Structural and Functional Analyses of Inhibition of Human Dihydroorotate Dehydrogenase by Antiviral Furocoumavirin.

Natural products are important sources of seed compounds for drug discovery. However, it has become difficult in recent years to discover new compounds with valuable pharmacological activities. On the other hand, among the vast number of natural products that have been isolated so far, a considerable number of compounds with specific biological activities are thought to be overlooked in screening that uses biological activity as an index. Therefore, it is conceivable that such overlooked useful compounds may be found by screening compound libraries that have been amassed previously through specific assays. Previously, NPD723, a member of the Natural Products Depository library comprised of a mixture of natural and non-natural products developed at RIKEN, and its metabolite H-006 were found to inhibit growth of various cancer cells at low nanomolar half-maximal inhibitory concentration. Subsequent analysis revealed that H-006 strongly inhibited human dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in the de novo pyrimidine biosynthetic pathway. Here, we elucidated the crystal structure of the DHODH-flavin mononucleotide-orotic acid-H-006 complex at 1.7 Å resolution to determine that furocoumavirin, the S-enantiomer of H-006, was the actual inhibitor. The overall mode of interaction of furocoumavirin with the inhibitor binding pocket was similar to that described for previously reported tight-binding inhibitors. However, the structural information together with kinetic characterizations of site-specific mutants identified key unique features that are considered to contribute to the sub-nanomolar inhibition of DHODH by furocoumavirin. Our finding identified new chemical features that could improve the design of human DHODH inhibitors.

Identification of DprE1 inhibitors for tuberculosis through integrated in-silico approaches.

Decaprenylphosphoryl-ß-D-ribose-2'-epimerase (DprE1), a crucial enzyme in the process of arabinogalactan and lipoarabinomannan biosynthesis, has become the target of choice for anti-TB drug discovery in the recent past. The current study aims to find the potential DprE1 inhibitors through in-silico approaches. Here, we built the pharmacophore and 3D-QSAR model using the reported 40 azaindole derivatives of DprE1 inhibitors. The best pharmacophore hypothesis (ADRRR_1) was employed for the virtual screening of the chEMBL database. To identify prospective hits, molecules with good phase scores (> 2.000) were further evaluated by molecular docking studies for their ability to bind to the DprE1 enzyme (PDB: 4KW5). Based on their binding affinities (< - 9.0 kcal/mole), the best hits were subjected to the calculation of free-binding energies (Prime/MM-GBSA), pharmacokinetic, and druglikeness evaluations. The top 10 hits retrieved from these results were selected to predict their inhibitory activities via the developed 3D-QSAR model with a regression coefficient (R2) value of 0.9608 and predictive coefficient (Q2) value of 0.7313. The induced fit docking (IFD) studies and in-silico prediction of anti-TB sensitivity for these top 10 hits were also implemented. Molecular dynamics simulations (MDS) were performed for the top 5 hit molecules for 200 ns to check the stability of the hits with DprE1. Based on their conformational stability throughout the 200 ns simulation, hit 2 (chEMBL_SDF:357100) was identified as the best hit against DprE1 with an accepted safety profile. The MD results were also in accordance with the docking score, MM-GBSA value, and 3D-QSAR predicted activity. The hit 2 molecule, (N-(3-((2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)phenyl)acrylamide) could serve as a lead for the discovery of a novel DprE1 inhibiting anti-TB drug.

Inhibitors of dermatan sulfate epimerase 1 decreased accumulation of glycosaminoglycans in mucopolysaccharidosis type I fibroblasts.

Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10 µM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients.

Py-CoMFA, docking, and molecular dynamics simulations of Leishmania (L.) amazonensis arginase inhibitors.

Leishmaniasis is a disease caused by a protozoan of the genus Leishmania, affecting millions of people, mainly in tropical countries, due to poor social conditions and low economic development. First-line chemotherapeutic agents involve highly toxic pentavalent antimonials, while treatment failure is mainly due to the emergence of drug-resistant strains. Leishmania arginase (ARG) enzyme is vital in pathogenicity and contributes to a higher infection rate, thus representing a potential drug target. This study helps in designing ARG inhibitors for the treatment of leishmaniasis. Py-CoMFA (3D-QSAR) models were constructed using 34 inhibitors from different chemical classes against ARG from L. (L.) amazonensis (LaARG). The 3D-QSAR predictions showed an excellent correlation between experimental and calculated pIC50 values. The molecular docking study identified the favorable hydrophobicity contribution of phenyl and cyclohexyl groups as substituents in the enzyme allosteric site. Molecular dynamics simulations of selected protein-ligand complexes were conducted to understand derivatives' interaction modes and affinity in both active and allosteric sites. Two cinnamide compounds, 7g and 7k, were identified, with similar structures to the reference 4h allosteric site inhibitor. These compounds can guide the development of more effective arginase inhibitors as potential antileishmanial drugs.

Design of FK866-Based Degraders for Blocking the Nonenzymatic Functions of Nicotinamide Phosphoribosyltransferase.

Nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic target for treating select cancers. There are two forms of NAMPT: intracellular NAMPT (iNAMPT, the rate-limiting enzyme in the mammalian NAD+ main synthetic pathway) and extracellular NAMPT (eNAMPT, a cytokine with protumorigenic function). Reported NAMPT inhibitors only inhibit iNAMPT and show potent activities in preclinical studies. Unfortunately, they failed to show efficacy due to futility and toxicity. We developed a series of FK866-based NAMPT-targeting PROTACs and identified LYP-8 as a potent and effective NAMPT degrader that simultaneously diminished iNAMPT and eNAMPT. Importantly, LYP-8 demonstrated superior efficacy and safety in mice when compared to the clinical candidate, FK866. This study highlights the importance and feasibility of applying PROTACs as a superior strategy for interfering with both the enzymatic function of NAMPT (iNAMPT) and nonenzymatic function of NAMPT (eNAMPT), which is difficult to achieve with conventional NAMPT inhibitors.

Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity.

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 µM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 µM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 µM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.