Gene network analysis combined with preclinical studies to identify and elucidate the mechanism of action of novel irreversible Keap1 inhibitor for Parkinson's disease.

The cysteine residues of Keap1 such as C151, C273, and C288 are critical for its repressor activity on Nrf2. However, to date, no molecules have been identified to covalently modify all three cysteine residues for Nrf2 activation. Hence, in this study, our goal is to discover new Keap1 covalent inhibitors that can undergo a Michael addition with all three cysteine residues. The Keap1's intervening region was modeled using Modeller v10.4. Covalent docking and binding free energy were calculated using CovDock. Molecular dynamics (MD) was performed using Desmond. Various in-vitro assays were carried out to confirm the neuroprotective effects of the hit molecule in 6-OHDA-treated SH-SY5Y cells. Further, the best hit was evaluated in vivo for its ability to improve rotenone-induced postural instability and cognitive impairment in male rats. Finally, network pharmacology was used to summarize the complete molecular mechanism of the hit molecule. Chalcone and plumbagin were found to form the necessary covalent bonds with all three cysteine residues. However, MD analysis indicated that the binding of plumbagin is more stable than chalcone. Plumbagin displayed neuroprotective effects in 6-OHDA-treated SH-SY5Y cells at concentrations 0.01 and 0.1 µM. Plumbagin at 0.1 µM had positive effects on reactive oxygen species formation and glutathione levels. Plumbagin also improved postural instability and cognitive impairment in rotenone-treated male rats. Our network analysis indicated that plumbagin could also improve dopamine signaling. Additionally, plumbagin could exhibit anti-oxidant and anti-inflammatory activity through the activation of Nrf2. Cumulatively, our study suggests that plumbagin is a novel Keap1 covalent inhibitor for Nrf2-mediated neuroprotection in PD.

Insights into the Biological Activities and Substituent Effects of Pyrrole Derivatives: The Chemistry-Biology Connection.

Pyrrole, with its versatile heterocyclic ring structure, serves as a valuable template for generating a diverse range of lead compounds with various pharmacophores. Researchers and scientists globally are intrigued by pyrrole and its analogs for their broad pharmacological potential, prompting thorough investigations aimed at advancing human welfare. This comprehensive review delves into the diverse activities exhibited by pyrrole compounds, encompassing their synthesis, reactions, and pharmacological properties alongside their derivatives. In addition to detailing the characteristics of pyrrole and its derivatives within the context of green chemistry, the review also examines microwave-assisted reactions. It provides insights into their chemical structures, natural occurrences, and potential applications across various domains. Furthermore, the article investigates structural alterations of pyrrole compounds and their implications on their functionality, highlighting their versatility as foundational elements for both functional materials and bioactive compounds. The review emphasizes the need for ongoing research and development in the field of pyrrole compounds to discover new activities and benefits.

Network-based drug repositioning of linagliptin as a potential agent for uterine fibroids targeting transforming growth factor-beta mediated fibrosis.

Uterine fibroid is the most common non-cancerous tumor with no satisfactory options for long-term pharmacological treatment. Fibroblast activation protein-α (FAP) is one of the critical enzymes that enhances the fibrosis in uterine fibroids. Through STITCH database mining, we found that dipeptidyl peptidase-4 inhibitors (DPP4i) have the potential to inhibit the activity of FAP. Both DPP4 and FAP belong to the dipeptidyl peptidase family and share a similar catalytic domain. Hence, ligands which have a binding affinity with DPP4 could also bind with FAP. Among the DPP4i, linagliptin exhibited the highest binding affinity (Dock score = -8.562 kcal/mol) with FAP. Our study uncovered that the differences in the S2 extensive-subsite residues between DPP4 and FAP could serve as a basis for designing selective inhibitors specifically targeting FAP. Furthermore, in a dynamic environment, linagliptin was able to destabilize the dimerization interface of FAP, resulting in potential inhibition of its biological activity. True to the in-silico results, linagliptin reduced the fibrotic process in estrogen and progesterone-induced fibrosis in rat uterus. Furthermore, linagliptin reduced the gene expression of transforming growth factor-ß (TGF-ß), a critical factor in collagen secretion and fibrotic process. Masson trichrome staining confirmed that the anti-fibrotic effects of linagliptin were due to its ability to reduce collagen deposition in rat uterus. Altogether, our research proposes that linagliptin has the potential to be repurposed for the treatment of uterine fibroids.

Side effects based network construction and drug repositioning of ropinirole as a potential molecule for Alzheimer's disease: an in-silico, in-vitro, and in-vivo study.

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Drug repositioning is a process of finding new therapeutic applications for existing drugs. One of the methods in drug repositioning is to use the side-effect profile of a drug to identify a new therapeutic indication. The drugs with similar side-effects may act on similar biological targets and could affect the same biochemical process. In this study, we explored the Food and Drug Administration-approved drugs using PROMISCUOUS database to find those that have adverse effects profile comparable with the ligands being studied or used to treat AD. Here, we found that the ropinirole, a dopamine receptor agonist, shared a maximum number of side-effects with the drugs proven beneficial for treating AD. Furthermore, molecular modelling demonstrated that ropinirole exhibited strong binding affinity (-9.313 kcal/mol) and best ligand efficiency (0.49) with sigma-1 receptor. Here, we observed that the quaternary amino group of ropinirole is essential for binding with sigma-1 receptor. Molecular dynamic simulation indicated that the movement of the carboxy-terminal helices (α4/α5) could play a major role in the receptor's physiological functions. The neurotoxicity induced by Aß25-35 in SH-SY5Y cells was reduced by ropinirole at concentrations 10, 30, and 50 µM. The effect on spatial learning and memory was examined in mice with Aß25-35 induced memory deficit using the radial arm maze. Ropinirole (10 and 20 mg/kg) significantly improved the short and long-term memories in the radial arm maze test. Our results suggest that ropinirole has the potential to be repositioned for AD treatment.Communicated by Ramaswamy H. Sarma.

Drug target of natural products and COVID-19: how far has science progressed?

The new coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] that caused a viral disease with a high risk of mortality (coronavirus disease 2019) was found toward the end of 2019. This was a significant acute respiratory syndrome. In a brief period, this virus spread throughout the entire planet, causing tremendous loss of life and economic damage. The process of developing new treatments takes time, and there are presently no recognized specific treatments to treat this infection. The most promising participants, who subsequently developed into prospective leads, were dropped from the clinical research in their latter phases. Medication that has previously acquired permission may only be repurposed for use for various medical reasons following a thorough investigation for safety and effectiveness. Because there are now no effective treatments available, natural products are being used haphazardly as antiviral medications and immunity boosters. The fundamental statement that most natural compounds have powerful antiviral action does not apply to SARS-CoV-2. Middle East respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus infections are inhibited by natural treatments. According to an in silico study, the virus' nonstructural proteins, including PLpro, Mpro, and RdRp, as well as structural proteins like the spike (S) protein, have been shown to have a strong affinity for several natural products and to be inhibited by them. The virus also suggests that it is a valid candidate for therapeutic research since it utilizes the intracellular angiotensin-converting enzyme 2 receptor of the host cell. In this study, interesting targets for SARS-CoV-2 medication development are explored, as well as the antiviral properties of some well-known natural compounds.

In Silico Drug Design of Anti-Breast Cancer Agents.

Cancer is a condition marked by abnormal cell proliferation that has the potential to invade or indicate other health issues. Human beings are affected by more than 100 different types of cancer. Some cancer promotes rapid cell proliferation, whereas others cause cells to divide and develop more slowly. Some cancers, such as leukemia, produce visible tumors, while others, such as breast cancer, do not. In this work, in silico investigations were carried out to investigate the binding mechanisms of four major analogs, which are marine sesquiterpene, sesquiterpene lactone, heteroaromatic chalcones, and benzothiophene against the target estrogen receptor-α for targeting breast cancer using Schrödinger suite 2021-4. The Glide module handled the molecular docking experiments, the QikProp module handled the ADMET screening, and the Prime MM-GB/SA module determined the binding energy of the ligands. The benzothiophene analog BT_ER_15f (G-score -15.922 Kcal/mol) showed the best binding activity against the target protein estrogen receptor-α when compared with the standard drug tamoxifen which has a docking score of -13.560 Kcal/mol. TRP383 (tryptophan) has the highest interaction time with the ligand, and hence it could act for a long time. Based on in silico investigations, the benzothiophene analog BT_ER_15f significantly binds with the active site of the target protein estrogen receptor-α. Similar to the outcomes of molecular docking, the target and ligand complex interaction motif established a high affinity of lead candidates in a dynamic system. This study shows that estrogen receptor-α targets inhibitors with better potential and low toxicity when compared to the existing market drugs, which can be made from a benzothiophene derivative. It may result in considerable activity and be applied to more research on breast cancer.

An Update on Poly(ADP-ribose) Polymerase I-A Brief Review.

Poly (ADP-ribose) polymerase 1 (PARP1) plays important roles in both DNA repair and transcription, and the interplay of these processes in relation to cellular function and disease states has not been well defined. The tumor-suppressor effects of PARP inhibitors have attracted significant interest in the development of novel cancer therapies. As PARP1 binding motifs may be readily found in promoter elements of DNA repair genes, the expanding role of PARP1 in DNA repair does not have to be independent of transcription. The discovery of ADP-ribose binding modules that bind to various forms of mono- and poly-ADP-ribose has provided important insights into how ADPribosylation regulates different cellular pathways. Among the four distinct PAR-binding modules discovered so far, it is the macrodomain alone that, in addition to possessing binding activity, in some instances, also supports a catalytic activity toward ADP-ribose derivatives. However, the development of PARP inhibitors as chemopotentiating agents has been limited by an increase in observed toxicity, mainly myelosuppression, necessitating dose reduction of the cytotoxic chemotherapeutic agent and the PARP inhibitor. Hence, it presents an opportunity to rationally develop combinations of PARP inhibitors with new classes of DNA repair inhibitors that are on the horizon and classical cytotoxic agents. Clinical trials of PARP inhibitors are investigating various uses of these approaches in cancer. Recent studies on the clinical significance of PARP1 inhibitors are discussed in this review. These recent research advances will inform the selection of patient populations who can benefit from the PARP inhibitor treatment and the development of effective drug combination strategies.

Revisiting the South Indian Traditional Plants against Several Targets of SARS-CoV-2 - An in silico Approach.

BACKGROUND: The south Indian Telugu states will celebrate a new year called 'Ugadi' which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. OBJECTIVE: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. METHODS: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. RESULTS: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, - 82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. CONCLUSION: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.

Ceftriaxone induces glial EAAT-2 promotor region via NF-kB conformational changes: An interaction analysis using HADDOCK.

Excitotoxicity, depletion of energy metabolites, and ionic imbalance are the major factors involved in neurodegeneration mediated through excitatory amino acid transporter-2 (EAAT-2) dysfunction in ischemic insult. Recent studies have revealed that ceftriaxone expresses EAAT-2 via nuclear transcription factor kappa-B (NF-kB) signaling pathway, stimulation of EAAT-2 expression in the ischemic, and excitotoxic conditions that could provide potential benefits to control neurodegeneration. In this study, we have predicted the in silico model for interaction between NF-kB and EAAT-2 promoter region to rule out the conformational changes for the expression of EAAT-2 protein. Using homology-built model of NF-kB, we identified ceftriaxone-induced conformational changes in gene locus -272 of DNA where NF-kB binding with EAAT-2 promoter region through protein-DNA docking calculation. The interaction profile and conformational dynamics occurred between ceftriaxone predocked and postdocked conformations of NF-kB with DNA employing HADDOCK 2.2 web server followed by 250 ns long all atom explicit solvent molecular dynamics simulations. Both the protein and DNA exhibited modest conformational changes with respect to HADDOCK score, energy terms (desolvation energy [Edesolv ]), van der waal energy (Evdw ), electrostatic energy (Eelec ), restraints energy (Eair ), buried surface area, root mean square deviation, RMSF, radius of gyration, total hydrogen bonds when ceftriaxone pre- and postdocked NF-kB conformations were bound to DNA. Hence, the conformational changes in the C-terminal domain could be the reason for EAAT-2 expression through ceftriaxone specific binding pocket of -272 of DNA.

Role of natural products towards the SARS-CoV-2: A critical review.

Despite the fact that various therapeutic compounds are being investigated, there is still a scarcity of effective and reliable therapeutic regimens to treat COVID-19. Ever since the COVID-19 pandemic, a diversity of traditional herbal treatments has been investigated to cure infected people, either alone or in conjunction with mainstream pharmaceuticals, with encouraging outcomes. In this article, we look at the latest research on the usage of natural products to alleviate the severity of COVID-19. To determine the activity of the natural products, act against SARS-CoV-2 to various targets like Mpro, ACE-II, papain-like, chymotrypsin-like proteases, and some antiviral targets. The processes underlying this preventative or therapeutic action are also examined. We used PubMed, Scopus, Google Scholar, and the WHO site to perform our review. The anti-SARS-CoV-2 impacts of various herbal extracts and purified compounds may be mediated via direct prevention of viral replication or entrance. Interestingly, certain items might avert SARS-CoV-2 from infecting human cells by blocking the ACE-2 protein or the serine protease TMPRRS2. Natural products have also been stated to suppress proteins intricate in the virus life cycle, like papain-like and chymotrypsin-like proteases. To conclude, natural products can be used alone or in combination as remedies or treatments for COVID-19. In addition, their compositions may provide insight into the development of effective and reliable antiviral drugs.

A Review on Acridines as Antiproliferative Agents.

Acridine derivatives have been thoroughly investigated and discovered to have multitarget qualities, inhibiting topoisomerase enzymes that regulate topological changes in DNA and interfering with DNA's vital biological function. This article discusses current progress in the realm of novel 9-substituted acridine heterocyclic compounds, including the structure and structure- activity connection of the most promising molecules. The IC50 values of the new compounds against several human cancer cell lines will also be presented in the publication. The review also looks into the inhibition of topoisomerase by polycyclic aromatic compounds. BACKGROUND: Acridine rings can be found in molecules used in many different areas, including industry and medicine. Nowadays, acridines with anti-bacterial activity are of research interest due to decreasing bacterial resistance. Some acridine derivatives showed antimalarial or antiviral activity. Acridine derivatives were also investigated for anti-tumor activity due to the interaction with topoisomerase II and DNA base pairs. Considering these possible uses of acridine derivatives, this work overviewed all significant structure performances for the specific action of these compounds. OBJECTIVE: The objective of this study is to review the activity of acridines as anti-proliferative agents. METHODS: This review is designed as acridines acting as topoisomerase I and II inhibitors/ poison, Acridines on the G-quadraplux interaction, Acridines with metal complexes, Acridines with quinacrine scaffold, Acridines with sulphur moiety. CONCLUSION: Although introduced in the 19th century, acridine derivatives are still of scientific interest. In this review, acridine derivatives with various biological activities (antiparasitic, antiviral, anti-bacterial, and antiproliferative) and their structure-activity relationship analyses are presented. Although several mechanisms of their action are known, the only important are discussed here. It can be concluded that the dominant mechanisms are DNA intercalation and interaction with enzymes.

Pyrazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer - An in-silico approach.

BACKGROUND: Breast cancer is one of the malignant tumours which mainly affect the female population. 20% of the cases of breast cancer are due to the over-expression of Human epidermal growth factor receptor-2 (HER2), which is the dominant tyrosine kinase receptor. In general, 9-anilinoacridine derivatives play an important role in antitumor activity due to their DNA-intercalating properties. OBJECTIVE: Some novel 9-anilinoacridines substituted with pyrazole moiety (1a-z) were designed and their HER2enzyme (PDB id-3PP0) inhibition activity was performed by molecular docking studies using the Glide module of Schrodinger suite 2019-4. METHODS: Glide module of the Schrodinger suite was used to perform docking studies; qikprop module was used for in-silico ADMET screening and the Prime-MMGBSA module was used for free binding energy calculations. Based on GLIDE scoring functions, we can determine the binding affinity of ligands (1a-z) towards HER2. RESULTS: The inhibitory activity of ligands against HER2 was mainly due to the strong hydrophobic and hydrogen bonding interactions. Almost all the compounds 1a-z exhibited a good binding affinity with Glide scores in the range of -4.9 to -9.75, when compared with the standard drugs CK0403 (-4.105) and Tamoxifen (-3.78). From the results of in-silico ADMET properties, it was evident that most of the compounds fell within the recommended values. MM-GBSA binding calculations of the most potent inhibitors were found to be more favourable. CONCLUSION: The results of in-silico studies provide strong evidence for the potential of valuable ligands in pyrazole substituted 9-anilinoacridines as HER2 inhibitors, and the compounds, 1v,s,r,d,a,o with significant Glide scores may produce significant anti-breast cancer activity.

Discovery of potential inhibitors for stat3: ligand based 3D pharmacophore, virtual screening, molecular docking, dynamic studies and in vitro evaluation.

A large analysis of the signal transducer and activator of transcription (STAT3) in cancer is currently being carried out. It regulates gene expression, which is required for normal cellular functions such as differentiation, cell growth, proliferation, survival, maturation, and immunity. A ligand-based pharmacophore model was created using 3 D QSAR pharmacophore generation methodology in Discovery studio 4.1 clients to imagine structurally diverse novel chemical entities as STAT3 inhibitors with improved efficacy. Chemical properties of 48 different derivatives were included in the training package. Hypo1 was chosen as the query model for screening 1,45,000 drug-like molecules from the SPECS database, with these molecules subjected to the Lipinski rule of 5, Verber's rule, and SMART filtration. After filtration, the molecule was examined further using molecular docking analysis on the active site of STAT3. The binding interaction(s) and pharmacophore mapping were used to select the 19 possible inhibitory molecules. These 19 hits were then tested for toxicity using the TOPKAT software. In MD simulations and MM-PBSA calculations, the tested compound specs 28 provided the best results, suggesting that this ligand has the ability to inhibit more effectively. Based in-silico finding 19 compounds are subjected to in vitro anticancer activity against MDA-MB-231 and MCF-7 cell lines. Based on results compounds specs 11 and specs 13 shows significant activity compared to other compounds and these compounds were subjected to apoptosis assay. The tested compounds induced morphologic changes were dose and time dependent by which all the tested compound exhibits stronger anti-tumor effects.Communicated by Ramaswamy H. Sarma.

Acridine as an Anti-Tumour Agent: A Critical Review.

This review summarized the current breakthroughs in the chemistry of acridines as anti-cancer agents, including new structural and biologically active acridine attributes. Acridine derivatives are a class of compounds that are being extensively researched as potential anti-cancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is restricted or even excluded as a result of side effects. The photocytotoxicity of propyl acridine acts against leukaemia cell lines, with C1748 being a promising anti-tumour drug against UDP-UGT's. CK0403 is reported in breast cancer treatment and is more potent than CK0402 against estrogen receptor-negative HER2. Acridine platinum (Pt) complexes have shown specificity on the evaluated DNA sequences; 9-anilinoacridine core, which intercalates DNA, and a methyl triazene DNA-methylating moiety were also studied. Acridine thiourea gold and acridinone derivatives act against cell lines such as MDA-MB-231, SK-BR-3, and MCF-7. Benzimidazole acridine compounds demonstrated cytotoxic activity against Dual Topo and PARP-1. Quinacrine, thiazacridine, and azacridine are reported as anti-cancer agents, which have been reported in the previous decade and were addressed in this review article.

Identification of Papain-Like Protease inhibitors of SARS CoV-2 through HTVS, Molecular docking, MMGBSA and Molecular dynamics approach.

Coronaviruses (CoVs) are a large group of enveloped positive sense single-stranded RNA viruses that can cause disease to humans. These are zoonotic having potential to cause large-scale outbreaks of infections widely causing morbidity and mortality. Papain-Like Protease (PLpro) is a cysteine protease, essential for viral replication and proliferation, as a highly conserved enzyme it cleaves peptide linkage between Nsp1, Nsp2, Nsp3, and Nsp4. As a valid therapeutic target, it stops viral reproduction and boosts host immune response thereby halting further spread of infection. In the purpose of identifying inhibitors targeting Papain-Like Proteases (PLpro) we initiated a high throughput virtual screening (HTVS) protocol using a SuperNatural Database. The XP docking results revealed that two compounds SN00334175 and SN00162745 exhibited docking scores of -10.58 kcal/mol and -9.93 kcal/mol respectively. The Further PRIME MMGB-SA studies revealed Van der Waal energy and hydrophobic energy terms as major contributors for total binding free energy. The 100 ns molecular dynamics simulation of SN00334175/7JN2 and SN00162745/7JN2 revealed that these complexes were stabilized with ligand binding forming interactions with Gly266, Asn267, Tyr268, Tyr273, Thr301 and Asp302, Lys157, Leu162, Asp164, Arg166, Glu167, Pro248 and Tyr264.

New stability chiral RP-HPLC method for degradation products determination in midodrine hydrochloride.

Enantiomeric resolution of the drug and complete separation from its degradation products was successfully achieved on a PAK IG-3 (150 × 4.6 mm i.d., 3 µm particle size) column, using UV detector at a wavelength of 290 nm, with mobile phase consisting of acetonitrile, 20 mM ammonium bicarbonate at the ratio of 95:05 (v/v), and a flow rate of 0.7 mL/min. In order to subjected to stress conditions, the drug has been exposed to alkaline, acidic, neutral, oxidative, and photolytic conditions. The products of degradation were well resolved from the main peak and proved the method's stability-indicating method. The method linear ranged between 10-110 µg/mL and 5-100 µg/mL for (+) and (-) midodrine enantiomers and regression analysis showed a correlation coefficient value (r2) of 0.999. The recovery of the method was found to be in the range of 99.1-101.2%. The detection limit for the (+) and (-) enantiomers was found to be 4 µg/mL and 1 µg/mL, respectively. The HPLC method was validated as per ICH guidelines with respect to specificity, precision, linearity, and robustness.

Identification of some novel oxazine substituted 9-anilinoacridines as SARS-CoV-2 inhibitors for COVID-19 by molecular docking, free energy calculation and molecular dynamics studies.

Coronavirus disease (COVID-19), a life-threatening disease, is caused by SARS-CoV-2. The targeted therapeutics of small molecules helps the scientific community to fight against SARS-CoV-2. In this article, some oxazine substituted 9-anilinoacridines (A1-A48) was designed by docking, MM-GBSA and molecular dynamics (MD) simulation studies for their COVID-19 inhibitory activity. The docking of ligands A1-A48 against SARS-CoV-2 (PDB ID: 5R82) are performed by using Glide module, in silico ADMET screening by QikProp module, binding energy using Prime MM-GB/SA module, MD simulation by Desmond module and atomic charges were derived by Jaguar module of Schrodinger suit 2019-4. Compound A38 has the highest G-score (-7.83) when compared to all the standard compounds which are proposed for COVID-19 treatment such as ritonavir (-7.48), lopinavir (-6.94), nelfinavir (-5.93), hydroxychloroquine (-5.47) and mataquine (-5.37). Compounds A13, A23, A18, A7, A48, A46, A32, A20, A1 and A47 are significantly active against SARS-CoV-2 main protease when compared with hydroxychloroquine and mataquine. The residues GLN19, THR24, THR25, THR26, LEU27, HIE41, SER46, MET49, ASN119, ASN142, HIE164, MET165, ASP187, ARG188 and GLN189 of SARS-CoV-2 main protease play a crucial role in binding with ligands. The in silico ADMET properties of the molecules are within the recommended values. The binding free energy was calculated using PRIME MM-GB/SA studies. From the ligands A38, A13, A23, A18, A7, A48 and A46 with significant Glide scores may produce significant COVID-19 activity for further development. Compound A38 was subjected to MD simulation at 100 ns to study the dynamic behaviour of protein-ligand complex.Communicated by Ramaswamy H. Sarma.

1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors.

BACKGROUND: 1,3,4-thiadiazolo pyrimidine is a lead molecule that is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity. OBJECTIVE: The objective of the study was to synthesize a series of 5-amino-7-(substituted aldehyde)-2[(naphthalene- 2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives and evaluate their possible in vitro and in vivo anticancer activity. METHODS: Herein, we report the synthetic scheme, which was followed for the preparation of a series of title compounds B1- B9 outlined in scheme 1. The intermediate 5-[(naphthalen-2- yloxy)methyl]-1,3,4-thiadiazolo- 2-amine was prepared by heating 2-naphthoxyacetic acid and thiosemicarbazide in the presence of phosphoryl chloride at a temperature of 65-75°C. The obtained compound reacted with malononitrile and an appropriate amount of aromatic and heteroaromatic aldehydes in refluxing ethanol yielded 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives (B1 - B9). The purity of the synthesized compounds was ensured by various spectral analyses. RESULTS: In in silico molecular docking studies, compounds B3 and B9 show binding affinity like known PARP1 inhibitor olaparib. The cellular evaluation indicates that the anticancer profile of compounds B1, B3, and B9 is significant when compared to the standard drug (olaparib) against MDA-MB-232 cell line and compounds B3, B6, and B7 are the most active against MCF-7 cell lines. The most active compound B3 was subjected to acute oral toxicity studies by OECD 423 guidelines and in vivo anti-cancer studies were carried out using DMBA induced model. CONCLUSION: The in silico docking study of the newly synthesized compounds was performed; the results showed good binding mode in the active site of PARP1 enzyme. In silico ADME properties of synthesized compounds were also studied and showed good drug-like properties.

Development and validation of LC/MS method for the determination of meclizine enantiomers in pharmaceutical formulations.

An enantiomeric separation of meclizine enantiomers by liquid chromatography with tandem mass spectrometry LC-MS method was developed and validated for the analysis of Meclizine enantiomers. Enantiomeric resolution of the drug products were successfully achieved on a Phenomenex® lux cellulose 1 C18 (250 mm × 4.6 mm i.d, 5 µm particle size) column with mobile phase consisting of acetonitrile: 5 mM ammonium format pH (5.5) adjusted with formic acid (90:10) (v/v), and a flow rate of 0.4 mL/min. The developed method provided linear responses within the concentration range 1-5 ng/mL, and regression analysis showed a correlation coefficient value (r2) of 0.999. The optimized mobile phase separated (+) Meclizine at 1.58 min and (-) Meclizine at 2.20 min, respectively. The LC/MS method was validated as per ICH guidelines with respect to specificity, precision, linearity and robustness. Limit of detection (LOD) and limit of quantification (LOQ) were found to be 1.0 ng/mL and 5.0 ng/mL respectively. The proposed method is suitable for analysis of meclizine enantiomers in pharmaceutical formulations and quality control analysis.

Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach.

BACKGROUND: In early 2020, many scientists are rushing to discover novel drugs and vaccines against the coronavirus, and treatments for COVID-19, because coronavirus disease 2019 (COVID-19), a life-threatening viral disease, affected first in China and quickly spread throughout the world. In this article, in silico studies have been performed to explore the binding modes of chemical constituents for natural remedies like Curcuma longa (turmeric) and Andrographis paniculata against COVID-19 (PDB ID 5R82) targeting coronavirus using Schrodinger suit 2019-4. The molecular docking studies are performed by the Glide module, in silico ADMET screening was performed by the QikProp module, and binding energy of ligands was calculated using the Prime MM-GB/SA module. RESULTS: The chemical constituents from turmeric like cyclocurcumin and curcumin and from Andrographis paniculata like andrographolide and dihydroxy dimethoxy flavone are significantly binding with the active site of SARS CoV-2 main protease with Glide score more than - 6 when compared to the currently used drugs hydroxychloroquine (- 5.47) and nelfinavir (- 5.93). When compared to remdesivir (- 6.38), cyclocurcumin from turmeric is significantly more active. The docking results of the compounds exhibited similar mode of interactions with SARS CoV-2. Main protease and the residues THR24, THR25, THR26, LEU27, SER46, MET49, HIE41, GLN189, ARG188, ASP187, MET165, HIE164, PHE181, and THR54 play a crucial role in binding with ligands. CONCLUSION: Based on in silico investigations, the chemical constituents from turmeric like cyclocurcumin and curcumin and from Andrographis paniculata like andrographolide and dihydroxy dimethoxy flavone, significantly binding with the active site of SARS CoV-2 main protease, may produce significant activity and be useful for further development.