Dual Anti-Inflammatory and Anticancer Activity of Novel 1,5-Diaryl Pyrazole Derivatives: Molecular Modeling, Synthesis, In Vitro Activity, and Dynamics Study.

A series of novel 1,5-diaryl pyrazole derivatives targeting the COX enzyme were designed by combined ligand and structure-based approach. The designed molecules were then further subjected to ADMET and molecular docking studies. Out of 34 designed compounds, the top-10 molecules from the computation studies were synthesized, characterized, and evaluated for COX-2 inhibition and anti-cancer activity. Initially, the target compounds were screened for the protein denaturation assay. The results of the top-five molecules T2, T3, T5, T6, and T9 were further subjected to in vitro COX-2 enzymatic assay and anti-cancer activity. As far as COX-2 inhibitory activity is considered, two compounds, T3 and T5, exhibited the half maximum inhibitory concentration (IC50) at 0.781 µM and 0.781 µM respectively. Further, the two compounds T3 and T5, when evaluated for COX-1 inhibition, exhibited excellent inhibitory activity with T3 IC50 of 4.655µM and T5 with IC50 of 5.596 µM. The compound T5 showed more significant human COX-2 inhibition, with a selectivity index of 7.16, when compared with T3, which had a selectivity index of 5.96. Further, in vitro anti-cancer activity was screened against two cancer cell lines in which compounds T2 and T3 were active against A549 cell lines and T6 was active against the HepG2 cell line. Stronger binding energy was found by comparing MM-PBSA simulations with molecular docking, which suggests that compounds T3 and T5 have a better possibility of being effective compounds, in which T5 showed higher binding affinity. The results suggest that these compounds have the potential to develop effective COX-2 inhibitors as anti-cancer agents.

Identification of indole-based natural compounds as inhibitors of PARP-1 against triple-negative breast cancer: a computational study.

Triple-negative breast cancer (TNBC) is the most aggressive kind of breast cancer known to mankind. It is a heterogeneous disease that is formed due to the missing estrogen, progesterone and human epidermal growth factor 2 receptors. Poly(ADP-ribose) polymerase-1 (PARP-1) protein helps in the development of TNBC by repairing the cancer cells, which proliferate and spread metastatically. To determine the potential PARP-1 inhibitors (PARPi), 0.2 million natural products from Universal Natural Product Database were screened using molecular docking and six hit compounds were selected based on their binding affinity towards PARP-1. The bio-availability and drug-like properties of these natural products were evaluated using ADMET analysis. Molecular dynamics simulations were conducted for these complexes for 200 ns to examine their structural stability and dynamic behaviour and further compared with the complex of talazoparib (TALA), an FDA-approved PARPi. Using MM/PBSA calculations, we conclude that the complexes HIT-3 and HIT-5 (-25.64 and -23.14 kcal/mol, respectively) show stronger binding energies with PARP-1 than TALA with PARP-1 (-10.74 kcal/mol). Strong interactions were observed between the compounds and hotspot residues, Asp770, Ala880, Tyr889, Tyr896, Ala898, Asp899 and Tyr907, of PARP-1 due to the existence of various types of non-covalent interactions between the compounds and PARP-1. This research offers critical information about PARPi, which could potentially be incorporated into the treatment of TNBC. Moreover, these findings were validated by comparing them with an FDA-approved PARPi.

Recent insights into the hepatoprotective potential of medicinal plants and plant-derived compounds.

Liver problems are a worldwide concern, and conventional medicinal therapies are ineffective. Hence, safeguarding the healthy liver is vital for good health and well-being. Infections due to virus, immune problems, cancer, alcohol abuse, and an overdose of drugs are some of the causes of liver diseases. Antioxidants derived from medicinal plants and conventional dietary sources can protect the liver from damages caused by oxidative stress system and various chemicals. Plants and plant-derived phytochemicals are appealing hepatoprotective agents since they have less side effects and still there is a lot of interest shown in using herbal tonics for treating liver disorders. This review therefore primarily focuses on newly discovered medicinal plants and compounds produced from plants that fall under the classifications of flavonoids, alkaloids, terpenoids, polyphenolics, sterols, anthocyanins, and saponin glycosides, all of which have the potential to be hepatoprotective. Hosta plantaginea, Ligusticum chuanxiong, Daniella oliveri, Garcinia mangostana, Solanum melongena, Vaccinium myrtillus, Picrorhiza kurroa, and Citrus medica are some potential plants having hepatoprotective effects. We conclude that these phytochemicals and the plant extracts listed above are used in the future to treat a variety of liver diseases, additional research is still needed to develop safer and more potent phytochemical drugs.

Discovery of novel HDAC8 inhibitors from natural compounds by in silico high throughput screening.

A class I histone deacetylase HDAC8 is associated with several diseases, including cancer, intellectual impairment and parasite infection. Most of the HDAC inhibitors that have so far been found to inhibit HDAC8 limit their efficacy in the clinic by producing toxicities. It is therefore very desirable to develop specific HDAC8 inhibitors. The emergence of HDAC inhibitors derived from natural sources has become quite popular. In recent decades, it has been shown that naturally occurring HDAC inhibitors have strong anticancer properties. A total of 0.2 million natural compounds were screened against HDAC8 from the Universal Natural Product Database (UNPD). Molecular docking was performed for these natural compounds and the top six hits were obtained. In addition, molecular dynamics (MD) simulations were used to evaluate the structural stability and binding affinity of the inhibitors, which showed that the protein-ligand complexes remained stable throughout the 100 ns simulation. MM-PBSA method demonstrated that the selected compounds have high affinity towards HDAC8. We infer from our findings that Hit-1 (-29.35 kcal mol-1), Hit-2 (-29.15 kcal mol-1) and Hit-6 (-30.28 kcal mol-1) have better binding affinity and adhesion to ADMET (absorption, distribution, metabolism, excretion and toxicity) characteristics against HDAC8. To compare our discussions and result in an effective way. We performed molecular docking, MD and MM-PBSA analysis for the FDA-approved drug romidepsin. The above results show that our hits show better binding affinity than the compound romidepsin (-12.03 ± 4.66 kcal mol-1). The important hotspot residues Asp29, Ile34, Trp141, Phe152, Asp267, Met274 and Tyr306 have significantly contributed to the protein-ligand interaction. These findings suggest that in vitro testing and additional optimization may lead to the development of HDAC8 inhibitors.Communicated by Ramaswamy H. Sarma.

Compounds from diverse natural origin against triple-negative breast cancer: A comprehensive review.

Triple-negative breast cancer (TNBC) is caused due to the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor 2 (HER2) expression. Triple-negative breast cancer is the most aggressive heterogeneous disease that is capable of producing different clones and mutations. Tumorigenesis in TNBC is caused due to the mutation or overexpression of tumor suppressor genes. It is also associated with mutations in the BRCA gene which is linked to hereditary breast cancer. In addition, PARP proteins and checkpoint proteins also play a crucial function in causing TNBC. Many cell signaling pathways are dysregulated in TNBC. Even though chemotherapy and immunotherapy are good options for TNBC treatment, the response rates are still low in general. Many phytochemicals that are derived from natural compounds have shown very good inhibitions for TNBC. Natural compounds have the great advantage of being less toxic, having lesser side effects, and being easily available. The secondary metabolites such as alkaloids, terpenoids, steroids, and flavonoids in natural products make them promising inhibitors of TNBC. Their compositions also offer vital insights into inhibitory action, which could lead to new cancer-fighting strategies. This review can help in understanding how naturally occurring substances and medicinal herbs decrease specific tumors and pave the way for the development of novel and extremely efficient antitumor therapies.

Antiviral activities of natural compounds and ionic liquids to inhibit the Mpro of SARS-CoV-2: a computational approach.

The recalcitrant spread of the COVID-19 pandemic produced by the novel coronavirus SARS-CoV-2 is one of the most destructive occurrences in history. Despite the availability of several effective vaccinations and their widespread use, this line of immunization often faces questions about its long-term efficacy. Since coronaviruses rapidly change, and multiple SARS-CoV-2 variants have emerged around the world. Therefore, finding a new target-based medication became a priority to prevent and control COVID-19 infections. The main protease (Mpro) is a salient enzyme in coronaviruses that plays a vital role in viral replication, making it a fascinating therapeutic target for SARS-CoV-2. We screened 0.2 million natural products against the Mpro of SARS-CoV-2 using the Universal Natural Product Database (UNPD). As well, we studied the role of ionic liquids (ILs) on the structural stabilization of Mpro. Cholinium-based ILs are biocompatible and used for a variety of biomedical applications. Molecular docking was employed for the initial screening of natural products and ILs against Mpro. To predict the drug-likeness features of lead compounds, we calculated the ADMET properties. We performed MD simulations for the selected complexes based on the docking outcomes. Using MM/PBSA approaches, we conclude that compounds NP-Hit2 (-25.6 kcal mol-1) and NP-Hit3 (-25.3 kcal mol-1) show stronger binding affinity with Mpro. The hotspot residues of Thr25, Leu27, His41, Met49, Cys145, Met165, and Gln189 strongly interacted with the natural compounds. Furthermore, naproxenate, ketoprofenate, and geranate, cholinium-based ILs strongly interact with Mpro and these ILs have antimicrobial properties. Our findings will aid in the development of effective Mpro inhibitors.

A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes.

Glucokinase is a key enzyme which converts glucose into glucose-6-phosphate in the liver and pancreatic cells of the human. In the liver, glucokinase promotes the synthesis of glycogen, and in the pancreas, it helps in glucose-sensitive insulin release. It serves as a "glucose sensor" and thereby plays an important role in the regulation of glucose homeostasis. Due to this activity, glucokinase is considered as an attractive drug target for type 2 diabetes. It created a lot of interest among the researchers, and several small molecules were discovered. The research work was initiated in 1990. However, the hypoglycemic effect, increased liver burden, and loss of efficacy over time were faced during clinical development. Dorzagliatin, a novel glucokinase activator that acts on both the liver and pancreas, is in the late-stage clinical development. TTP399, a promising hepatoselective GK activator, showed a clinically significant and sustained reduction in glycated hemoglobin with a low risk of adverse effects. The successful findings generated immense interest to continue further research in finding small molecule GK activators for the treatment of type 2 diabetes. The article covers different series of GK activators reported over the past decade and the structural insights into the GK-GK activator binding which, we believe will stimulate the discovery of novel GK activators to treat type 2 diabetes.

Synergistic effects of curcumin and its analogs with other bioactive compounds: A comprehensive review.

Curcumin, as a natural compound, extracted from plant Curcuma longa, is abundant in the Indian subcontinent and Southeast Asia, and have been used in a diverse array of pharmacological activities. Although curcumin has some limitations like low stability and low bioavailability, it has been proved that this compound induced apoptosis signaling and is also known to block cell proliferation signaling pathway. Recently, extensive research has been carried out to study the application of curcumin as a health improving agent, and devise new methods to overcome to the curcumin limitations and incorporate this functional ingredient into foods. Combinational chemotherapy is one of the basic strategies is using for 60 years for the treatment of various health problems like cancer, malaria, inflammation, diabetes and etc. Molecular hybridization is another strategy to make multi-pharmacophore or conjugated drugs with more synergistic effect than the parent compounds. The aim of this review is to provide an overview of the pharmacological activity of curcumin and its analogs in combination with other bioactive compounds and cover more recent reports of anti-cancer, anti-malarial, and anti-inflammatory activities of these analogs.

Discovery of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors by Ligand-based Virtual High Throughput Screening.

Virtual screening has become one of the important tools in the discovery of novel hits for the given target. The present study reports the successful application of ligand-based virtual screening method for the discovery of novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. We generated a ligand query model with pharmacophore features from the reported VEGFR-2 inhibitors using vROCS tool and performed virtual screening. Among the 2.4 million lead like molecules of ZINC database screened, nineteen prioritized compounds were purchased from Enamine and ChemBridge and tested for VEGFR-2 inhibitory activity using Promega's ADP-Glo™ kinase assay. Experimental validation led to the discovery of four compounds 3, 7, 10, and 13. Compound 10 exhibited moderate inhibitory activity with the IC50 value of 19.3 µM. Molecular docking was performed for these compounds and the predicted binding modes reported in this paper may further guide to explore the possible structural changes to get more potent VEGFR-2 inhibitors.

Targeting severe acute respiratory syndrome-coronavirus (SARS-CoV-1) with structurally diverse inhibitors: a comprehensive review.

Coronaviruses, which were discovered in 1968, can lead to some human viral disorders, like severe acute respiratory syndrome (SARS), Middle East respiratory syndrome-related (MERS), and, recently, coronavirus disease 2019 (COVID-19). The coronavirus that leads to COVID-19 is rapidly spreading all over the world and is the reason for the deaths of thousands of people. Recent research has revealed that there is about 80% sequence homology between the coronaviruses that cause SARS and COVID-19. Considering this fact, we decided to collect the maximum available information on targets, structures, and inhibitors reported so far for SARS-CoV-1 that could be useful for researchers who work on closely related COVID-19. There are vital proteases, like papain-like protease 2 (PL2pro) and 3C-like protease (3CLpro), or main protease (Mpro), that are involved in and are essential for the replication of SARS coronavirus and so are valuable targets for the treatment of patients affected by this type of virus. SARS-CoV-1 NTPase/helicase plays an important role in the release of several non-structural proteins (nsps), so it is another essential target relating to the viral life cycle. In this paper, we provide extensive information about diverse molecules with anti-SARS activity. In addition to traditional medicinal chemistry outcomes, HTS, virtual screening efforts, and structural insights for better understanding inhibitors and SARS-CoV-1 target complexes are also discussed. This study covers a wide range of anti-SARS agents, particularly SARS-CoV-1 inhibitors, and provides new insights into drug design for the deadly SARS-CoV-2 virus.

Molecular mechanisms of curcumin and its analogs in colon cancer prevention and treatment.

Colorectal cancer remains to be the most prevalent malignancy in humans and 1.5 million men and women living in the United States are diagnosed with colorectal cancer, with a predicted 145,600 new cases to be diagnosed in 2019. Curcuminoids and its synthetic analogs are now of interest due to their bioactive attributes, especially their action as anticancer activity in various cancer cell line models. Several in vivo and in vitro studies have substantially proved their anticancer activities against colon cancer cell lines. Curcumin analogues like IND-4, FLLL, GO-Y030 and C086 have demonstrated to produce greater cytotoxicity when experimentally studied and study results from many have been suggested to be the same. Combination of curcumin with therapeutic cancer agents like tolfenamic acid, 5-fluorouracil, resveratrol and dasatinib showed improved cytotoxicity and chemotherapeutic effect. The results propose that employment of curcumin with novel drug delivery systems like liposome, micelles and nanoparticle have been performed which could improve the therapeutic efficacy against colon cancer. The present review highlights the mechanism of action, synergistic effect and novel delivery methods to improve the therapeutic potential of curcumin.

Synthesis, evaluation of cytotoxic properties of promising curcumin analogues and investigation of possible molecular mechanisms.

Curcumin is a popular, plant-derived compound that has been extensively investigated for diverse range of biological activities. Anticancer activity against various types of cancers and high-safety profile associated with curcumin makes it very attractive. In this study, we report the synthesis and evaluation of pyrazole and click chemistry curcumin analogues for Head and Neck cancer. MTT assay against head and neck cancer cell lines CAL27 and UM-SCC-74A revealed the micromolar potency of the synthesized compounds. To determine the possible molecular mechanisms, effect of these analogues in the expression of pSTAT3, pFAK, pERK1/2 and pAKT was studied. Interestingly, compounds 2 and 5 significantly inhibited the pSTAT3 (Tyr 705) phosphorylation. As far as other compounds, they showed potent cytotoxicity against CAL27; however, these compounds did not show any activity on pSTAT3 phosphorylation at IC50 concentration level. Molecular docking studies revealed the possible binding mode of pyrazole compound 2 in the SH2 domain of STAT3.

Therapeutic potential of chemically modified siRNA: Recent trends.

Small interfering RNAs (siRNAs) are one of the valuable tools to investigate the functions of genes and are also used for gene silencing. It has a wide scope in drug discovery through in vivo target validation. siRNA therapeutics are not optimal drug-like molecules due to poor bioavailability and immunogenic and off-target effects. To overcome the challenges associated with siRNA therapeutics, identification of appropriate chemical modifications that improves the stability, specificity and potency of siRNA is essential. This review focuses on the various chemical modifications and their implications in siRNA therapy.

Pterocarpan scaffold: A natural lead molecule with diverse pharmacological properties.

Phytoalexins are substances produced by plants that act as potent inhibitors of pathogens. Pterocarpans are biologically active isoflavonoids most commonly found in the family Fabaceae that have the ability to act as phytoalexins. It is made up of a tetracyclic ring system possessing benzofuran-benzopyran. A very great number of pterocarpans have been isolated from natural sources and they are proved to have significant biological activities such as anti-microbial, anti-cancerous, anti-inflammatory and anti-malarial activities. Recently, pterocarpans gained lot of attention because of the broad range of anti-cancer activities in various cancer cell lines such as breast, leukemia, cervical, lung, colon and melanoma. Interestingly, pterocarpans exhibited inhibitory potency against many enzymes such as PTP1B, Neuraminidase, and α-glycosidase. In addition, they were shown to have anti-estrogenic and anti-diabetic activities. This review is a comprehensive inventory of the structures and sources of pterocarpans and it emphasizes on the biological evaluations of pterocarpans from various plant sources and their scope as a lead molecule.

Molecular mechanisms of curcumin and its semisynthetic analogues in prostate cancer prevention and treatment.

Primary prostate cancer, also known as prostate adenocarcinoma (PCa), is a devastating cancer in men worldwide. Europe and developing countries of Asia have fewer reported cases of prostate cancer compared to increasing cases in the United States with higher incidence in Black men. Risk factors associated with prostate cancer are aging, genetics, lifestyle, high body mass index as well as carcinogenic exposure to carbon-containing fuels, tobacco, and charbroiled meats. Hormone therapy and radical prostatectomy are commonly implemented treatments. The >20.000 prostate cancer deaths of 2013 suggest that there exists a need for enhanced chemopreventive and therapeutic agents for prostate cancer treatment. Fruits, vegetables, and red wines contain high levels of polyphenolic levels. Consumption of these products may provide chemoprevetion of PCa. Curcumin, the major compound from the turmeric rhizome Curcuma longa has long been used for medicinal purposes as an antiseptic and wound healing. This review focuses on curcumin's therapeutic effectiveness in vitro and in vivo in prostate cancer models. The review will highlight the mechanisms of actions of curcumin in the signaling pathways of prostate cancer.

Computer-aided design of negative allosteric modulators of metabotropic glutamate receptor 5 (mGluR5): Comparative molecular field analysis of aryl ether derivatives.

The metabotropic glutamate receptors (mGlu receptors) have emerged as attractive targets for number of neurological and psychiatric disorders. Recently, mGluR5 negative allosteric modulators (NAMs) have gained considerable attention in pharmacological research. Comparative molecular field analysis (CoMFA) was performed on 73 analogs of aryl ether which were reported as mGluR5 NAMs. The study produced a statistically significant model with high correlation coefficient and good predictive abilities.

Ligand-protein cross-docking with water molecules.

The accuracy of ligand-protein docking may be affected by the presence of water molecules on the surface of the protein. Cross-docking simulations have been performed on a number of ligand-protein complexes for various proteins whose crystal structures contain water molecules in their binding sites. Only common sets of water molecules found in the binding site of the proteins were considered. A statistically significant overall increase in accuracy was observed when water molecules were included in cross-docking simulations. These results confirm the importance of including water molecules whenever possible in ligand-protein docking simulations.

Nature and position of functional group on thiopurine substrates influence activity of xanthine oxidase--enzymatic reaction pathways of 6-mercaptopurine and 2-mercaptopurine are different.

Xanthine oxidase-catalyzed hydroxylation reactions of the anticancer drug 6-mercaptopurine (6-MP) and its analog 2-mercaptopurine (2-MP) as well as 6-thioxanthine (6-TX) and 2-thioxanthine (2-TX) have been studied using UV-spectroscopy, high pressure liquid chromatography, photodiode array, and liquid chromatography-based mass spectral analysis. It is shown that 6-MP and 2-MP are oxidatively hydroxylated through different pathways. Enzymatic hydroxylation of 6-MP forms 6-thiouric acid in two steps involving 6-TX as the intermediate, whereas 2-MP is converted to 8-hydroxy-2-mercaptopurine as the expected end product in one step. Surprisingly, in contrast to the other thiopurines, enzymatic hydroxylation of 2-MP showed a unique hyperchromic effect at 264 nm as the reaction proceeded. However, when 2-TX is used as the substrate, it is hydroxylated to 2-thiouric acid. The enzymatic hydroxylation of 2-MP is considerably faster than that of 6-MP, while 6-TX and 2-TX show similar rates under identical reaction conditions. The reason why 2-MP is a better substrate than 6-MP and how the chemical nature and position of the functional groups present on the thiopurine substrates influence xanthine oxidase activity are discussed.

6-(N-benzoylamino)purine as a novel and potent inhibitor of xanthine oxidase: inhibition mechanism and molecular modeling studies.

The inhibition of xanthine oxidase (XO) activity by the purine analogue 6-(N-benzoylamino)purine was evaluated and compared with the standard inhibitor, allopurinol and the parent compound adenine. 6-(N-benzoylamino)purine is a highly potent inhibitor of XO (IC50 = 0.45 microM) and comparable to allopurinol (IC50 = 0.80 microM). Furthermore, 6-(N-benzoylamino)purine neither produced any enzymatic superoxide nor reduced XO by an electron transfer reaction unlike allopurinol. 6-(N-benzoylamino)purine (Ki = 0.0475 microM) is about 10000-fold more potent as a XO inhibitor compared to the only known purine analogue 8-bromoxanthine (Ki = 400 microM). 6-(N-Benzoylamino)purine is a competitive inhibitor of XO and the inhibition was not completely reversed even at 100 microM xanthine concentration. The calculated interaction energy [Ecomplex - (Eligand + Eprotein)] of -30.5, -22.6, and -17.2 kcal/mol, respectively, of 6-(N-benzoylamino)purine, 8-bromoxanthine and the parent compound adenine provided the rationale for the better enzyme inhibitory activity of 6-(N-benzoylamino)purine. To understand the role of the benzamido group in the inhibition process, molecular docking studies were carried out and it was revealed that the hydrogen bonding interactions involving N-7 of the purine ring and the N-H of Arg880, N-H of the purine ring and OH of Thr1010, as well as non-bonded interactions of the benzamido group of 6-(N-benzoylamino)purine with amino acid residues Gly799, Glu802, Phe914, Ala1078, Ala1079 and Glu1261 in the active site of XO play an important role in the stabilization of the E-I complex.

Design, synthesis, biological evaluation and molecular docking of curcumin analogues as antioxidant, cyclooxygenase inhibitory and anti-inflammatory agents.

Curcuminoids were isolated from Curcuma longa and their pyrazole and isoxazole analogues were synthesized and evaluated for antioxidant, COX-1/COX-2 inhibitory and anti-inflammatory activities. The designed analogues significantly enhance COX-2/COX-1 selectivity and possess significant anti-inflammatory activity in carrageenan induced rat paw edema assay. Pyrazole, isoxazole analogues of curcumin (4 and 7) exhibited higher antioxidant activity than trolox. Molecular docking study revealed the binding orientations of curcumin analogues in the active sites of COX and thereby helps to design novel potent inhibitors.