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BACKGROUND Ohno and Colleagues proposed an approach for predicting drug-drug interactions (DDIs) mediated by cytochrome P450 (CYP) 3A4 based on the use of the ratio of the inhibited to non-inhibited area under the plasma concentration time curve (AUC) of substrates to estimate the fraction of the dose metabolized via CYP3A4 (contribution ratio, CR) and the in vivo inhibitory potency of a perpetrator (inhibition ratio, IR). This study evaluated the performance of this approach on DDIs mediated by CYP2C8 inhibitors. RESEARCH DESIGN AND METHODS Initial estimates of CR and IR of CYP2C8 substrates and inhibitors were calculated for 33 DDI in vivo studies. The approach was externally validated with 17 additional studies. Bayesian orthogonal regression was used to refine the estimates of the parameters. Assessment of prediction success was conducted by plotting observed versus predicted AUC ratios. RESULTS Final estimates of CRs and IRs were obtained for 19 CYP2C8 substrates and 23 inhibitors, respectively. The method demonstrated good predictive capacity, with only two values outside of the prespecified limits. CONCLUSIONS The approach may help to adapt dose regimens for CYP2C8 substrates when given in combination with CYP2C8 inhibitors and to map the potential DDIs of new molecular entities.

NLRP3 inflammasome has recently attracted much attention as a potentially druggable target to develop potential therapeutics for inflammatory and neurodegenerative disorders. In our continuing studies, structure–activity relationship studies were conducted based on a newly identified NLRP3 inhibitor, YQ-II-128, from our laboratory to understand the structural features and improve aqueous solubility. The results revealed that steric interactions at the propoxyl and amide domain of YQ-II-128 are important for the observed inhibitory potency on the NLRP3 inflammasome. The results also identified the amide domain to incorporate polar moieties to improve solubility and potentially pharmacokinetic properties. As a result, analog 10 was identified as a selective NLRP3 inhibitor with comparable potency while significantly improved aqueous solubility. Collectively, these findings strongly encourage further optmization of 10 to develop analogs with improved pharmacokinetic properties as potential NLRP3-targted therapeutics.

doi:10.1021/jacs.0c11336, Photopharmacology addresses the challenge of drug selectivity and side effects through creation of photoresponsive molecules activated with light with high spatiotemporal precision. This is achieved through incorporation of molecular photoswitches and photocages into the pharmacophore. However, the structural basis for the light-induced modulation of inhibitory potency in general is still missing, which poses a major design challenge for this emerging field of research. Here we solved crystal structures of the glutamate transporter homologue Glt$_{Tk}$ in complex with photoresponsive transport inhibitors���azobenzene derivative of TBOA (both in trans and cis configuration) and with the photocaged compound ONB-hydroxyaspartate. The essential role of glutamate transporters in the functioning of the central nervous system renders them potential therapeutic targets in the treatment of neurodegenerative diseases. The obtained structures provide a clear structural insight into the origins of photocontrol in photopharmacology and lay the foundation for application of photocontrolled ligands to study the transporter dynamics by using time-resolved X-ray crystallography.

The bacterial quorum sensing (QS) system is a target for non-lethal antibacterial agents that do not encourage the development of resistance. QS inhibitors commonly contain a polar "head" moiety and a lipidic "tail" moiety. In this work, we synthesised novel QS inhibitor candidates in which the lipidic "tail" is decorated with stereospecifically positioned fluorine atoms. The presence of fluorine is shown to bias the molecules into distinctive conformations that are pre-organised for binding to the QS receptor. This translates into significant increases in QS inhibitory potency.

Chalcones, a class of natural lipase inhibitors, have received substantial attention from researchers in recent years. Although many kinds of chalcones are typically distributed in G. inflata, there is little literature about the anti-lipase activity of G. inflata extracts (GIEs). In the present study, a ligand fishing strategy for fast screening of lipase inhibitors from GIEs was thus proposed. Porcine pancreatic lipase (PPL) was firstly immobilized on carboxyl modified Fe3O4 magnetic nanoparticles (MNPs) to obtain PPL functionalized MNPs (PPL@MNPs), and then the PPL@MNPs were incubated with a bioactive fraction to fish out the ligands. Eight ligands were obtained and identified as one flavone together with seven chalcones. Licochalcone A, licochalcone D and licochalcone E inhibited pancreatic lipase (PL) with IC50 of 4.9, 3.2 and 5.8 μM, respectively. Meanwhile, investigation of the structure-activity relationship also revealed that isopentenyl and hydroxyl substituents at ring A were essential for the noncovalent inhibitory potency of the chalcones.

Botulinum neurotoxin serotype A (BoNT/A) is an important therapeutic target owing to its extremely potent nature, but also has potential use as a biowarfare agent. Currently, no therapeutic exists to reverse the long-lasting paralysis caused by BoNT/A. Herein, we describe the identification of 3-hydroxy-1,2-dimethylpyridine-4(1H)-thione (3,4-HOPTO) as a metal binding warhead for the inhibition of BoNT/A1. An initial screen of 96 metal binding fragments identified three derivatives containing the 3,4-HOPTO scaffold to inhibit the BoNT/A1 light chain (LC) at >95% at 1 mM. Additional screening of a 3,4-HOPTO sub-library identified structure–activity relationships (SARs) between N-substituted 3,4-HOPTO derivatives and the BoNT/A1 LC. Subsequent synthesis was conducted to improve on inhibitory potency – achieving low μM biochemical IC50 values. Representative compounds were evaluated in a cellular-based assay and showed promising μM activity.

The inhibition of dipeptidyl peptidase IV (DPP-IV, E.C.3.4.14.5) is well recognized as a new avenue for the treatment of Type 2 diabetes (T2D). Until now, peptide-like DDP-IV inhibitors have been shown to normalize the blood glucose concentration in T2D subjects. To the best of our knowledge, there is yet no computational model for predicting and analyzing DPP-IV inhibitory peptides using sequence information. In this study, we present for the first time a simple and easily interpretable sequence-based predictor using the scoring card method (SCM) for modeling the bioactivity of DPP-IV inhibitory peptides (iDPPIV-SCM). Particularly, the iDPPIV-SCM was developed by employing the SCM method together with the propensity scores of amino acids. Rigorous independent test results demonstrated that the proposed iDPPIV-SCM was found to be superior to those of well-known machine learning (ML) classifiers (e.g., k-nearest neighbor, logistic regression, and decision tree) with demonstrated improvements of 2-11, 4-22, and 7-10% for accuracy, MCC, and AUC, respectively, while also achieving comparable results to that of the support vector machine. Furthermore, the analysis of estimated propensity scores of amino acids as derived from the iDPPIV-SCM was performed so as to provide a more in-depth understanding on the molecular basis for enhancing the DPP-IV inhibitory potency. Taken together, these results revealed that iDPPIV-SCM was superior to those of other well-known ML classifiers owing to its simplicity, interpretability, and validity. For the convenience of biologists, the predictive model is deployed as a publicly accessible web server at http://camt.pythonanywhere.com/iDPPIV-SCM. It is anticipated that iDPPIV-SCM can serve as an important tool for the rapid screening of promising DPP-IV inhibitory peptides prior to their synthesis.

Selective inhibitors of protein kinase CK2 with significant cytotoxicity on tumor cells based on a 2-aminothiazole scaffold were described recently. Here, these studies are supplemented with representative CK2α/CK2α' complex structures. They reveal that the 2-aminothiazole-based inhibitors occupy the ATP cavity, whereas preliminary data had indicated an allosteric binding site. The crystal structure findings are corroborated by subsequent enzyme kinetic studies; their atomic-resolution quality provides the basis for future optimization of these promising CK2 inhibitors.

Background: In the recent years, histamine H3 receptor (H3R) has been receiving increasing attention in pharmacotherapy of neurological disorders. The aim of the current study was to investigate structural requirements for the prediction of H3 antagonistic activity using quantitative structure-activity relationship (QSAR) and molecular docking techniques. Methods: To this end, genetic algorithm coupled partial least square and stepwise multiple linear regression methods were employed for developing a QSAR model. The obtained QSAR model was stringently assessed using different validation criteria. Results: The generated model indicated that connectivity information and mean absolute charge are two important descriptors for the prediction of H3 antagonistic activity of the studied compounds. To gain insight into the mechanism of interaction between studied molecules and H3R, molecular docking was performed. The most important residues involved in the ligand-receptor interactions were identified. Conclusion: The result of current study can be used for designing of new H3 antagonist and proposing structural modifications to improve H3 inhibitory potency.

Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one‐step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi‐valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one‐step. Next, we performed anchor‐based pharmacophore screening of the libraries and resynthesized top‐ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases., Anchored, yet sailing fast: Here we present the workflow for anchor‐centered docking of tailor‐made virtual libraries and its application to the design, synthesis and biological evaluation of aspartic protease inhibitors. Multi‐component reaction chemistry allows for the rapid synthesis of derivatives, and crystallographic studies show the binding mode of the identified inhibitors.

Background: The presence of bone metastases in renal cell carcinoma (RCC) negatively affects patients’ survival. Data from clinical trials has highlighted a significant benefit of cabozantinib in bone metastatic RCC patients. Here, we evaluated the antitumor effect of cabozantinib in coculture models of renal cell carcinoma (RCC) and osteoblasts (OBs) to investigate whether and how its antiproliferative activity is influenced by OBs. Methods: Bone/RCC models were generated, coculturing green fluorescent protein (GFP)-tagged Caki-1 and 786-O cells with human primary OBs in a “cell–cell contact” system. RCC proliferation and the OB molecular profile were evaluated after the cabozantinib treatment. Results: The Caki-1 cell proliferation increased in the presence of OBs (p &lt, 0.0001), while the 786-O cell growth did not change in the coculture with the OBs. The cabozantinib treatment reduced the proliferation of both the Caki-1 (p &lt, 0.0001) and 786-O (p = 0.03) cells cocultured with OBs. Intriguingly, the inhibitory potency of cabozantinib was higher when Caki-1 cells grew in presence of OBs compared to a monoculture (p &lt, 0.001), and this was similar in 786-O cells alone or cocultured with OBs. Moreover, the OB pretreatment with cabozantinib “indirectly” inhibited Caki-1 cell proliferation (p = 0.040) without affecting 786-O cell growth. Finally, we found that cabozantinib was able to modulate the OB gene and molecular profile inhibiting specific proliferative signals that, in turn, could affect RCC cell growth. Conclusions: Overall, the “direct” effect of cabozantinib on OBs “indirectly” increased its antitumor activity in metastatic RCC Caki-1 cells but not in the primary 786-O model.

Catalpol, a famous molecule of iridoids, possesses extensive pharmacological activities. Our studies found that compounds with low-polarity substituents at the 6-O position of catalpol exhibited higher NF-κB inhibitory potency than catalpol. However, catalpol derivatives are not much focused. Here this review provides extensive coverage of naturally occurring catalpol derivatives discovered from 1888 until 2018. It covers their distribution, chemotaxonomic significance, chemical structures, and bioactivities from more than 200 peer-reviewed articles, and highlights the structure-activity relationship of catalpol derivatives.

In the presence of Fe3+ cation, S-nitrosoglutathione (GSNO) loses the potency to inhibit catalase in the system containing hemoglobin (an NO trap) with iron chelator or -SH inhibitor (a “sulfhydric poison” Hg2+). In the absence of hemoglobin, the inhibitory potency is retained in both cases. These properties are characteristic of dinitrosyl-iron complexes containing ferrous iron and thiols (DNIC/RSH). Since the potency to inhibit catalase results from the presence of -NO group, its loss in the presence of hemoglobin relates probably to transfer of this group to hemoglobin. The nitrosothiols are relatively stable compounds, so their ability to release NO under the action of iron chelators, which is characteristic of DNIC/RSH, can have important physiological implications, because the role of such chelators can be played by some endogenous agents as well. Thus, release of NO from the donor compounds can be controlled and regulated. Probably, the agents such as nitrosothiol+Fe3+ are the major constituents in the pool of nitroso compounds.

Human dihydroorotate dehydrogenase (DHODH), the enzyme that catalyzes the rate‐limiting step in de novo pyrimidine biosynthesis, is considered to be an attractive target for potential treatment of autoimmune disease and cancer. Here, we present a novel class of human DHODH inhibitors with high inhibitory potency. The high‐resolution crystal structures of human DHODH complexed with various agents reveal the details of their interactions. Comparisons with the binding modes of teriflunomide and brequinar provide insights that may facilitate the development of new inhibitors targeting human DHODH.

The aim of this study is to evaluate the inhibitory potency of ethanol extracts of Aloe vera plant on Acetylcholinesterase AchE and Monoamine Oxidase MAO enzymes activities in vitro .Enzyme kinetic studies using ( Michaelis-Menten and Lineweaver-Burk equations ) were used to establish the type of inhibition. The Aloe vera extract showed a significantly higher percentage of inhibition. The activity observed in this study tends to validate some of the traditional claims of using Aloe vera as a functional food, and used as a treatment for many diseases that are related to the nervous system and it has no side effects such as some medications الخلاصة الهدف من هذه الدراسة تقييم فعالية مثبطة في مستخلص الإيثانول من نبات الاوليفيرا على نشاط الانزيمات أسيتيل كولين استريز و أوكسيديز احادي الامين في المختبر . استخدمت الدراسات الحركية الإنزيمية باستخدام معادلات (مايكل مينتين و لينويفر- بورك ) لتحديد نوع التثبيط. وأظهرت مستخلصات الاوليفيرا أعلى نسبة تثبيط بشكل ملحوظ. ان النشاط الذي لوحظ في هذه الدراسة يميل إلى التحقق من صحة بعض المطالبات التقليدية في استخدام الاوليفيرا كغذاء وظيفي ، وتستخدم كعلاج لكثير من الأمراض التي ترتبط بالجهاز العصبي وليس لها أي آثار جانبية ملحوظة كما في بعض الأدوية

Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.

Chemical investigation of the plant endophytic fungus Pestalotiopsis sp. afforded two new butenolides, pestalolides B and C (1 and 2), two new diphenyl ethers, pestalotethers E and F (3 and 4), together with seven known compounds (5–11). Their structures were established by extensive spectroscopic analyses and the absolute configuration of 1 was further confirmed by ECD calculation. Structurally, compound 1 represents the first example of a new type of butenolide derivatives, bearing an unprecedented carbon scaffold having 13 carbon atoms. Compounds 1–4 were evaluated for the cytotoxic activities, and compound 1 showed remarkable inhibitory potency against human tumor HL60, U87MG, MDA-MB-231, and HEP-3B cell lines, with IC50 values of 1.42, 5.90, 5.90, and 4.29 μM, respectively.

Photocaging of a tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase (PKA) with a nitrodibenzofuran-based group fully abolished its inhibitory potency. The affinity difference between the photocaged and the active inhibitor was over 5 orders of magnitude. The photocaged inhibitor disrupted the PKA holoenzyme in cell lysates upon photolysis under a 398 nm LED.

Scientific investigation on essential oils composition and the related biological profile are continuously growing. Nevertheless, only a few studies have been performed on the relationships between chemical composition and biological data. Herein, the investigation of 61 assayed essential oils is reported focusing on their inhibition activity against Microsporum spp. including development of machine learning models with the aim of highlining the possible chemical components mainly related to the inhibitory potency. The application of machine learning and deep learning techniques for predictive and descriptive purposes have been applied successfully to many fields. Quantitative composition–activity relationships machine learning-based models were developed for the 61 essential oils tested as Microsporum spp. growth modulators. The models were built with in-house python scripts implementing data augmentation with the purpose of having a smoother flow between essential oils’ chemical compositions and biological data. High statistical coefficient values (Accuracy, Matthews correlation coefficient and F1 score) were obtained and model inspection permitted to detect possible specific roles related to some components of essential oils’ constituents. Robust machine learning models are far more useful tools to reveal data augmentation in comparison with raw data derived models. To the best of the authors knowledge this is the first report using data augmentation to highlight the role of complex mixture components, in particular a first application of these data will be for the development of ingredients in the dermo-cosmetic field investigating microbial species considering the urge for the use of natural preserving and acting antimicrobial agents.

Bacterial sialidases (SA) are validated drug targets expressed by common human pathogens such as Streptococcus pneumoniae, Vibrio cholerae, or Clostridium perfringens. Noncovalent inhibitors of bacterial SA capable of reaching the submicromolar level are rarely reported. In this work, multi‐ and polyvalent compounds are developed, based on the transition‐state analogue 2‐deoxy‐2,3‐didehydro‐N‐acetylneuraminic (DANA). Poly‐DANA inhibits the catalytic activity of SA from S. pneumoniae (NanA) and the symbiotic microorganism B. thetaiotaomicron (BtSA) at the picomolar and low nanomolar levels (expressed in moles of molecules and of DANA, respectively). Each DANA grafted to the polymer surpasses the inhibitory potential of the monovalent analogue by more than four orders of magnitude, which represents the highest multivalent effect reported so far for an enzyme inhibition. The synergistic interaction is shown to operate exclusively in the catalytic domain, and not in the flanked carbohydrate‐binding module (CBM). These results offer interesting perspectives for the multivalent inhibition of other SA families lacking a CBM, such as viral, parasitic, or human SA. 27;9

COVID-19 is the most unanticipated incidence of 2020 affecting the human population worldwide. Currently, it is utmost important to produce novel small molecule anti-SARS-CoV-2 drugs urgently that can save human lives globally. Based on the earlier SARS-CoV and MERS-CoV infection along with the general characters of coronaviral replication, a number of drug molecules have been proposed. However, one of the major limitations is the lack of experimental observations with different drug molecules. In this article, 70 diverse chemicals having experimental SARS-CoV-2 3CLproinhibitory activity were accounted for robust classification-based QSAR analysis statistically validated with 4 different methodologies to recognize the crucial structural features responsible for imparting the activity. Results obtained from all these methodologies supported and validated each other. Important observations obtained from these analyses were also justified with the ligand-bound crystal structure of SARS-CoV-2 3CLpro enzyme. Our results suggest that molecules should contain a 2-oxopyrrolidine scaffold as well as a methylene (hydroxy) sulphonic acid warhead in proper orientation to achieve higher inhibitory potency against SARS-CoV-2 3CLpro. Outcomes of our study may be able to design and discover highly effective SARS-CoV-2 3CLpro inhibitors as potential anticoronaviral therapy to crusade against COVID-19.

A series of 1-(substituted phenoxyacetoxy)-1-(furan-2-yl)methylphosphonates as potential inhibitor of pyruvate dehydrogenase complex (PDHc) was synthesized and studied. Some of them were found to be a kind of effective plant PDHc inhibitor with higher inhibitory potency against broadleaf plant PDHc. The most effective compound II-17 showed good herbicidal activity against broadleaf weeds at 100–300 g ai/ha and it was very safe for rice, maize, and wheat even at the rate of 800–1200 g ai/ha. The recent field trials at different regions in China further showed that II-17 (O,O-dimethyl 1-(2,4-dichlorophenoxyacetoxy)-1-(furan-2-yl)methylphosphonate, HWS) could be applied to control a broad spectrum of broad-leaved weeds at the rate of 135–450 g ai/ha for postemergence in maize fields by using the formulation of 30% EC (Emulsifiable concentrate) or 30% powder. This compound as dicot PDHc inhibitor displayed the good utility as a selective postemergence herbicide.

Alzheimer's disease (AD) is one of the most common neurodegenerative causes of dementia, the pathology of which is still not much clear. It′s challenging to discover the disease modifying agents for the prevention and treatment of AD over the years. Emerging evidence has been accumulated to reveal the crucial role of up‐regulated glutaminyl cyclase (QC) in the initiation of AD. In the current study, the QC inhibitory potency of a library consisting of 1621 FDA‐approved compounds was assessed. A total of 54 hits, 3.33 % of the pool, exhibited QC inhibitory activities. The Ki of the top 5 compounds with the highest QC inhibitory activities were measured. Among these selected hits, compounds affecting neuronal signaling pathways and other mechanisms were recognized. Moreover, several polyphenol derivatives with QC inhibitory activities were also identified. Frameworks and subsets contained in these hits were analyzed. Taken together, our results may contribute to the discovery and development of novel QC inhibitors as potential anti‐AD agents., Up‐regulated glutaminyl cyclase (QC) has a crucial role in the initiation of Alzheimer's disease (AD).The QC inhibitory potency of a library containing 1621 FDA‐approved compounds was investigated. Molecule scaffolds and motifs contained in these hits (3.33 % of the pool) are suggested to be combined into the design of new fragment like libraries targeting QC. This approach may support the development of novel QC inhibitors as potential anti‐AD agents.

The anthraquinones are a huge group of natural compounds, and one of the compounds from that group is 1, 8-dihydroxy-3-methoxy-6-methyl- anthracene-9, 10-dione (parietin, known as physcion as well). The parietin is produced by various plants such as R. crispus and R. japonicus Houtt., as well as many fungi such as Aspergillus spp., Penicillium spp., and Alternaria spp. It is well known that parietin possesses antitumor activity, antioxidant activity, antimutagenic activity, topoisomerase II inhibitory activity, in vitro antiviral activity against poliovirus, and antifungal activity. Knowing these facts it can be supposed that they can found application in medicinal chemistry. A study was conducted to explore the antioxidative and inhibitory potency of parietin. Density functional theory (DFT) is a powerful tool used for examining the antioxidative mechanisms. The Gaussian 09 program package is used to perform all electronic calculations. The equilibrium geometries of the parent molecule of parietin, its radical cation, radicals, and anions are calculated using the B3LYP-D3BJ functional in conjunction with the 6-311++G(d, p) basis set. The influence of water as a polar solvent (ε = 78.36) was estimated using the CPCM solvation model. Inhibitory potency of parientin is estimated by applying molecular docking simulations. For this purpose AutoDock 4.0 software is used, and inhibitory potency of parietin is estimated toward main protease Mpro from SARS-CoV-2.