scholarly journals Discovery of Chalcone-Based Hybrid Structures as High Affinity and Site-Specific Inhibitors Against COVID-19; a Study Based on Various Host-Based and Viral Targets

2021 ◽  
Author(s):  
Mehdi Valipour ◽  
Hamid Irannejad
Keyword(s):  
Antiviral Agent ◽  
Inhibitory Effect ◽  
Therapeutic Agents ◽  
Chemical Library ◽  
Site Specific ◽  
Computational Screening ◽  
Significant Inhibitory Effect ◽  
Main Fragment ◽  
Antiviral Targets ◽  
Viral Reproduction

Abstract 3-Chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are at the forefront of attention for finding therapeutic agents for the treatment of COVID-19. In addition, proper modulation of host-based antiviral targets (HBATs) has also been highlighted by scientists as a promising approach for the suppression of the SARS-CoV-2. Previous studies indicated that some natural-based chalcones have significant inhibitory effect on the coronavirus enzymes 3CLpro and PLpro as well as modulation of some HBATs. In this study, a computational screening was performed to investigate the affinity of our compound library consisting of 757 chalcone-based structures (CHA-1 to CHA-757) for inhibiting the 3CLpro and PLpro enzymes, and also against twelve selected host-based targets. The twelve selected HBATs were chosen based on their involvement in viral reproduction. Our results indicated that CHA-12 (VUF 4819) is the most potent and a multi-target inhibitor in our chemical library over all viral and host-based targets. Correspondingly, CHA-384 and its congeners containing ureide moieties were found to be potent and selective 3CLpro inhibitors, and benzotriazole moiety in CHA-37 was found to be a main fragment for inhibiting the 3CLpro and PLpro. Surprisingly, our results were fully consistent with recent reports on the site-specific 3CLpro inhibitors. The results also indicate that the ureide and sulfonamide moieties are integral fragments for the optimum 3CLpro inhibition while occupying the S1 and S3 subsites. Finding the multi-target inhibitor CHA-12, previously reported as a LTD4 antagonist for the treatment of inflammatory pulmonary diseases, prompted us to suggest it as a concomitant antiviral agent for relieving respiratory symptoms and suppressing COVID-19 infection.

Potential antidiarrheal agents: 1-(11-Cyano-6,11-dihydrodibenzo[b,e]thiepin-11-yl-alkyl)- and 1-(10-cyano-10,11-dihydrodibenzo[b,f]thiepin-10-yl-alkyl)-4-substituted piperidines

1985 ◽  
Vol 50 (5) ◽  
pp. 1089-1096 ◽  
Author(s):  
Karel Šindelář ◽  
Jan Metyš ◽  
Miroslav Protiva
Keyword(s):  
Inhibitory Effect ◽  
Substitution Reactions ◽  
Significant Inhibitory Effect

Substitution reactions of 11-(2-bromoethyl)- and 11-(3-bromopropyl)-6,11-dihydrodibenzo[b,e]thiepin-11-carbonitrile and further of 10-(2-bromoethyl)- and 10-(3-bromopropyl)-10,11-dihydrodibenzo[b,f]thiepin-10-carbonitrile with ethyl 4-phenylpiperidine-4-carboxylate, 4-phenylpiperidin-4-ol, 4-(2-tolyl)piperidin-4-ol, 4-(4-fluorophenyl)piperidin-4-ol, 4-(2-oxobenzimidazolin-1-yl)-piperidine and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one afforded the tricyclic piperidinoalkyl nitriles IV-XIII which are cyclic analogues of the antidiarrheal agents diphenoxylate (I) and loperamide (III). Out of the compounds prepared only IV and XI showed a significant inhibitory effect towards diarrhea elicited by intravenously administered serotonin in mice.

scholarly journals A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ying Liu ◽  
Wenjie Liu ◽  
Ziqiang Yu ◽  
Yan Zhang ◽  
Yinghua Li ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoporosis Treatment ◽  
Inhibitory Effect ◽  
Specific Gene ◽  
Actin Ring ◽  
Treatment Target ◽  
Significant Inhibitory Effect ◽  
Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

scholarly journals Toward Homogenous Antibody Drug Conjugates Using Enzyme-Based Conjugation Approaches

2021 ◽  
Vol 14 (4) ◽  
pp. 343
Author(s):  
Ahmad Fawzi Hussain ◽  
Armin Grimm ◽  
Wenjie Sheng ◽  
Chaoyu Zhang ◽  
Marwah Al-Rawe ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Amino Acid Residues ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Site Specific ◽  
Drug Conjugates ◽  
Complement Dependent Cytotoxicity ◽  
Antibody Conjugates ◽  
Specific Antigens ◽  
Antibody Conjugate ◽  
Therapeutic Mechanisms

In the last few decades, antibody-based diagnostic and therapeutic applications have been well established in medicine and have revolutionized cancer managements by improving tumor detection and treatment. Antibodies are unique medical elements due to their powerful properties of being able to recognize specific antigens and their therapeutic mechanisms such as blocking specific pathways, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Furthermore, modification techniques have paved the way for improving antibody properties and to develop new classes of antibody-conjugate-based diagnostic and therapeutic agents. These techniques allow arming antibodies with various effector molecules. However, these techniques are utilizing the most frequently used amino acid residues for bioconjugation, such as cysteine and lysine. These bioconjugation approaches generate heterogeneous products with different functional and safety profiles. This is mainly due to the abundance of lysine and cysteine side chains. To overcome these limitations, different site-direct conjugation methods have been applied to arm the antibodies with therapeutic or diagnostics molecules to generate unified antibody conjugates with tailored properties. This review summarizes some of the enzyme-based site-specific conjugation approaches.

scholarly journals Combined Ensemble Docking and Machine Learning in Identification of Therapeutic Agents with Potential Inhibitory Effect on Human CES1

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2747 ◽  
Author(s):  
Eliane Briand ◽  
Ragnar Thomsen ◽  
Kristian Linnet ◽  
Henrik Berg Rasmussen ◽  
Søren Brunak ◽  
...  
Keyword(s):  
Machine Learning ◽  
Drug Interactions ◽  
Scoring Function ◽  
Docking Study ◽  
Inhibitory Effect ◽  
Therapeutic Agents ◽  
Learning Approaches ◽  
Ensemble Docking ◽  
Ic50 Values

The human carboxylesterase 1 (CES1), responsible for the biotransformation of many diverse therapeutic agents, may contribute to the occurrence of adverse drug reactions and therapeutic failure through drug interactions. The present study is designed to address the issue of potential drug interactions resulting from the inhibition of CES1. Based on an ensemble of 10 crystal structures complexed with different ligands and a set of 294 known CES1 ligands, we used docking (Autodock Vina) and machine learning methodologies (LDA, QDA and multilayer perceptron), considering the different energy terms from the scoring function to assess the best combination to enable the identification of CES1 inhibitors. The protocol was then applied on a library of 1114 FDA-approved drugs and eight drugs were selected for in vitro CES1 inhibition. An inhibition effect was observed for diltiazem (IC50 = 13.9 µM). Three others drugs (benztropine, iloprost and treprostinil), exhibited a weak CES1 inhibitory effects with IC50 values of 298.2 µM, 366.8 µM and 391.6 µM respectively. In conclusion, the binding site of CES1 is relatively flexible and can adapt its conformation to different types of ligands. Combining ensemble docking and machine learning approaches improves the prediction of CES1 inhibitors compared to a docking study using only one crystal structure.

scholarly journals New Inhibitory Effects of Cilnidipine on Microglial P2X7 Receptors and IL-1β Release: An Involvement in its Alleviating Effect on Neuropathic Pain

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 434
Author(s):  
Tomohiro Yamashita ◽  
Sawako Kamikaseda ◽  
Aya Tanaka ◽  
Hidetoshi Tozaki-Saitoh ◽  
Jose M. M. Caaveiro ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
High Throughput Screening ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Inhibitory Effect ◽  
Intrathecal Administration ◽  
Chemical Library ◽  
P2x7 Receptors ◽  
Approved Drugs ◽  
Cardinal Symptom

P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states in the central nervous system and in various diseases, including neuropathic pain. Thus, P2X7R may represent a potential therapeutic target. In the present study, we screened a chemical library of clinically approved drugs (1979 compounds) by high-throughput screening and showed that the Ca2+ channel blocker cilnidipine has an inhibitory effect on rodent and human P2X7R. In primary cultured rat microglial cells, cilnidipine inhibited P2X7R-mediated Ca2+ responses and IL-1β release. Moreover, in a rat model of neuropathic pain, the intrathecal administration of cilnidipine produced a reversal of nerve injury-induced mechanical hypersensitivity, a cardinal symptom of neuropathic pain. These results point to a new inhibitory effect of cilnidipine on microglial P2X7R-mediated inflammatory responses and neuropathic pain, proposing its therapeutic potential.

scholarly journals Synthesis and Evaluation of Biological Activity of New Arylphosphoramidates

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Amal Thebti ◽  
M. A. K. Sanhoury ◽  
H-I. Ouzari ◽  
T. Barhoumi-slimi
Keyword(s):  
Biological Activity ◽  
Ir Spectroscopy ◽  
Acetylcholinesterase Activity ◽  
Inhibitory Effect ◽  
Bacterial Strains ◽  
Significant Inhibitory Effect ◽  
Subsequent Addition

The synthesis of new substituted arylphosphoramidates is performed in two steps through phosphorylation of the corresponding alcohols followed by aminolysis. The formation of the desired phosphoramidates depends on the subsequent addition of the two alcohols with the amine being added at the last step. The products were obtained in 58–95% yields. They were characterized mainly by multinuclear (1H, 13C, 31P, and 19F) NMR and IR spectroscopy. In addition, the antimicrobial and antiacetylcholinesterase activities were evaluated. The results showed acetylcholinesterase activity by some compounds, whilst no significant inhibitory effect against the tested bacterial strains has been recorded.

scholarly journals Effects of fragrance compounds on growth of the silkworm Bombyx mori

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11620
Author(s):  
Zhen-peng Kai ◽  
Yanwei Qiu ◽  
Xue-wei Zhang ◽  
Shan-shan Chen
Keyword(s):  
Bombyx Mori ◽  
Endocrine System ◽  
Inhibitory Effect ◽  
Ethyl Vanillin ◽  
Abnormal Growth ◽  
Significant Inhibitory Effect ◽  
Ecological Problems ◽  
Musk Xylene ◽  
Fragrance Compounds

Due to the contamination and biological toxicity of some fragrance compounds, the environmental and ecological problems of such compounds have attracted more and more attention. However, studies of the toxicity of fragrance compounds for insects have been limited. The toxicity of 48 fragrance compounds for the silkworm Bombyx mori were investigated in this study. All of the fragrance compounds examined had no acute toxicity for B. mori larvae, but eight of them (menthol, maltol, musk xylene, musk tibeten, dibutyl sulfide, nerolidol, ethyl vanillin, and α-amylcinnamaldehyde) exhibited chronic and lethal toxicity with LC50 values from 20 to 120 µM. In a long-term feeding study, musk tibeten, nerolidol, and musk xylene showed significant growth regulatory activity. They were also extremely harmful to the cocooning of B. mori, resulting in small, thin, and loose cocoons. Two important insect hormones, namely, juvenile hormone (JH) and 20-hydroxyecdysone (20-E), were quantified in hemolymph following chronic exposure to musk tibeten, nerolidol, and musk xylene, respectively. Musk tibeten significantly increased JH titer and decreased the 20-E titer in hemolymph, and musk xylene had a significant inhibitory effect on JH titer and increased 20-E titer. Although nerolidol had no effect on hormone levels, exogenous JH mimic nerolidol increased the physiological effects of JH and significantly slowed the growth rate of B. mori larvae. The results showed that these fragrance compounds could interfere with the insect endocrine system, leading to death and abnormal growth. The risk to insects of residual fragrance compounds in the environment is worthy of attention.

scholarly journals Using Lactobacillus as Probiotic to Inhibit Growth and Adhesion of Proteus mirabilis Causing Urinary Tract Infection

2008 ◽  
Vol 2 (1) ◽  
pp. 19-32
Author(s):  
Ghydaa H. A al-jeboury ◽  
Abdul Wahed Baker
Keyword(s):  
Urinary Tract Infection ◽  
Lactic Acid ◽  
Urinary Tract ◽  
Epithelial Cell ◽  
Tract Infection ◽  
Proteus Mirabilis ◽  
Inhibitory Effect ◽  
Adhesion Property ◽  
Significant Inhibitory Effect ◽  
Urine Specimens

The aim of the study was to use lactic acid bacteria (LAB), as probiotic, to treat growth and adhesion property of Proteus mirabilis isolated from patients suffering from urinary tract infection (UTI). For this purpose, one P. mirabilis isolate (P.M.9) was selected out of 9 isolates obtained from 150 urine specimens. Due to its resistance to 11 antibiotics tested, this isolate was treated with three-fold concentrated filtrates of two lactobacillus isolates (as probiotic). Results after treatment, showed that the filtrates exhibited significant inhibitory effect against the pathogenic P.M.9 and its adhesion property especially when only an average of 3-10 bacteria /cell were adhered to each epithelial cell compared to 44-55 bacteria/cell.

Isoflavones from Camphorosma lessingii Inhibit the Organic Anion Transporters OAT1 and OAT3

Planta Medica ◽  
2018 ◽  
Vol 85 (03) ◽  
pp. 225-230 ◽  
Author(s):  
Xinhui Wang ◽  
Dujuan Wang ◽  
Xue Wang ◽  
Manana Khutsishvili ◽  
Kamilla Tamanyan ◽  
...  
Keyword(s):  
Organic Anion ◽  
Inhibitory Effect ◽  
Spectroscopic Methods ◽  
Organic Anion Transporters ◽  
One Dimensional ◽  
Anion Transporters ◽  
Significant Inhibitory Effect ◽  
Phytochemical Investigation ◽  
The Family ◽  
First Time

AbstractPhytochemical investigation of Camphorosma lessingii has resulted in the isolation of four previously unreported isoflavones (1–4) and eight known compounds (5–12). Nine of these compounds (1–6, 8–10) are reported for the first time from members of the family Amaranthaceae. The structures of all isolated compounds were determined by spectroscopic methods, primarily one-dimensional and two-dimensional nuclear magnetic resonance and mass spectrometry. The absolute configuration of 6 was confirmed by circular dichroism. Inhibition of the organic anion transporters, OAT1 and OAT3, by the isolated compounds was evaluated. Among them, 7, 2′-dihydroxy- 6,8-dimethoxyisoflavone (1), 2′-hydroxy-6,7,8-trimethoxyisoflavone (2), 6,2′-dihydroxy-7,8-dimethoxyisoflavone (3), and 7-methoxyflavone (5) showed a significant inhibitory effect on 6-carboxyfluorescein uptake mediated by OAT1 and OAT3.

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