N-Substituted piperazine-coupled imidazo[2,1-b]thiazoles as inhibitors of Mycobacterium tuberculosis: Synthesis, evaluation, and docking studies.

An innovative series of N-substituted piperazine-linked imidazothiazole derivatives 7(a-x) were synthesized, and their antitubercular effectiveness was evaluated. A three-step reaction sequence involving the condensation of 1,3-dichloroacetone and thiourea, coupling with substituted piperazines to give the intermediates 5(a-d) and cyclization with substituted α-bromoacetophenones produced the desired imidazothiazole derivatives 7(a-x) in excellent yields. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv resulted in 7k (minimum inhibitory concentration [MIC]: 0.78 µg/mL) and 7g and 7h (MIC: 1.56 µg/mL) as potent hit compounds. Further, the docking studies of the promising compounds 7k, 7g, and 7h revealed that the best molecular interactions are with the DprE1 in complex with sulfonyl PBTZ of M. tuberculosis as the target protein (PDB ID: 6G83).

Structure-based virtual screening of natural compounds against wild and mutant (R1155K, A1156T and D1168A) NS3-4A protease of Hepatitis C virus.

NS3-4A, a serine protease, is a primary target for drug development against Hepatitis C Virus (HCV). However, the effectiveness of potent next-generation protease inhibitors is limited by the emergence of mutations and resulting drug resistance. To address this, in this study a structure-based drug design approach is employed to screen a large library of 7320 natural compounds against both wild-type and mutant variants of NS3-4A protease. Telaprevir, a widely used protease inhibitor, was recruited as the control drug. The top 10 compounds with favorable binding affinities underwent drug-likeness evaluation. Based on ADMET studies, complexes of NP_024762 and NP_006776 were selected for molecular dynamic simulations. Principal component analysis (PCA) was employed to explore the conformational space and protein dynamics of the protein-ligand complex using a Free Energy Landscape (FEL) approach. The cosine values obtained from FEL analysis ranged from 0 to 1, and eigenvectors with cosine values below 0.2 were chosen for further analysis. To forecast binding free energies and evaluate energy contributions per residue, the MM-PBSA method was employed. The results highlighted the crucial role of amino acids in the catalytic domain for the binding of the protease with phytochemicals. Stable associations between the top compounds and the target protease were confirmed by the formation of hydrogen bonds in the binding pocket involving residues: His1057, Gly1137, Ser1139, and Ala1157. These findings suggest the potential of these compounds for further validation through biological evaluation.Communicated by Ramaswamy H. Sarma.

Virtual Screening of a Marine Natural Product Database for In Silico Identification of a Potential Acetylcholinesterase Inhibitor.

Alzheimer's disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future.

Ligand-based pharmacophore modeling and QSAR approach to identify potential dengue protease inhibitors.

The viral disease dengue is transmitted by the Aedes mosquito and is commonly seen to occur in the tropical and subtropical regions of the world. It is a growing public health concern. To date, other than supportive treatments, there are no specific antiviral treatments to combat the infection. Therefore, finding potential compounds that have antiviral activity against the dengue virus is essential. The NS2B-NS3 dengue protease plays a vital role in the replication and viral assembly. If the functioning of this protease were to be obstructed then viral replication would be halted. As a result, this NS2B-NS3 proves to be a promising target in the process of anti-viral drug design. Through this study, we aim to provide suggestions for compounds that may serve as potent inhibitors of the dengue NS2B-NS3 protein. Here, a ligand-based pharmacophore model was generated and the ZINC database was screened through ZINCPharmer to identify molecules with similar features. 2D QSAR model was developed and validated using reported 4-Benzyloxy Phenyl Glycine derivatives and was utilized to predict the IC50 values of unknown compounds. Further, the study is extended to molecular docking to investigate interactions at the active pocket of the target protein. ZINC36596404 and ZINC22973642 showed a predicted pIC50 of 6.477 and 7.872, respectively. They also showed excellent binding with NS3 protease as is evident from their binding energy of -8.3and -8.1 kcal/mol, respectively. ADMET predictionsofcompounds have shown high drug-likeness. Finally, the molecular dynamic simulations integrated with MM-PBSA binding energy calculations confirmedboth identified ZINC compounds as potential hit moleculeswith good stability.

Computational design of MmpL3 inhibitors for tuberculosis therapy.

Tuberculosis is a chronic communicable disease caused by Mycobacterium tuberculosis (Mtb) and spreads from lungs to lymphatic system. The cell wall of mycobacterium plays a prominent role in maintaining the virulence and pathogenicity and also acts as prime target for drug discovery. Hence, this study has put into emphasis with target MmpLs (Mycobacterial membrane proteins Large) which are significant for the growth and survival of Mycobacterium tuberculosis. MmpLs belongs to the resistance, nodulation and division (RND) protein superfamily. MmpL3 is the only MmpL deemed essential for the replication and viability of mycobacterial cells. For the study, we have selected SQ109 derivatives as Mmpl3 inhibitor, which holds non-covalent property. Structure-based pharmacophore model of MmpL3 target protein with SQ109 as co-crystallized ligand (PDB: 6AJG) was generated to screen the ligand database. Compounds with decent fitness score and pharmacophoric features were compared with standard drug and taken for molecular docking studies. Further prime molecular mechanics-Poisson-Boltzmann surface area (MM-GBSA) and induced fit calculations identified potential molecules for further drug-likeness screening. Overall computational calculations identified ZINC000000016638 and ZINC000000003594 as potential in silico MmpL3 inhibitors. Molecular dynamics simulations integrated with MM-PBSA free energy calculations identified that MmpL3-ZINC000000016638 complex was more stable. Study can be further extended for synthesis and biological evaluation, derivatization of active compound to identify potential and safe lead compounds for effective tuberculosis therapy.

miRNA and antisense oligonucleotide-based α-synuclein targeting as disease-modifying therapeutics in Parkinson's disease.

α-synuclein is the synaptic protein majorly involved in neuronal dysfunction and death and it is well known for the last two decades as a hallmark of Parkinson's disease. Alpha-synuclein is involved in neurodegeneration mediated through various neurotoxic pathways, majorly including autophagy or lysosomal dysregulation, mitochondrial disruption, synaptic dysfunction, and oxidative stress. Moreover, the alpha-synuclein aggregation has been associated with the development of several neurodegenerative conditions such as various forms of Parkinson's disease. The recent discovery in oligonucleotide chemistry has developed potential alpha-synuclein targeting molecules for the treatment of neurodegenerative diseases. The present review article focuses on recent advances in the applications of oligonucleotides acting via alpha-synuclein targeting mechanisms and their implication in combating Parkinson's disease. Moreover, the article emphasizes the potential of miRNAs, and antisense oligonucleotides and the challenges associated with their use in the therapeutical management of Parkinson's disease.

A comprehensive review on acridone based derivatives as future anti-cancer agents and their structure activity relationships.

The development of drug resistance and severe side-effects has reduced the clinical efficacy of the existing anti-cancer drugs available in the market. Thus, there is always a constant need to develop newer anti-cancer drugs with minimal adverse effects. Researchers all over the world have been focusing on various alternative strategies to discover novel, potent, and target specific molecules for cancer therapy. In this direction, several heterocyclic compounds are being explored but amongst them one promising heterocycle is acridone which has attracted the attention of medicinal chemists and gained huge biological importance as acridones are found to act on different therapeutically proven molecular targets, overcome ABC transporters mediated drug resistance and DNA intercalation in cancer cells. Some of these acridone derivatives have reached clinical studies as these heterocycles have shown huge potential in cancer therapeutics and imaging. Here, the authors have attempted to compile and make some recommendations of acridone based derivatives concerning their cancer biological targets and in vitro-cytotoxicity based on drug design and novelty to increase their therapeutic potential. This review also provides some important insights on the design, receptor targeting and future directions for the development of acridones as possible clinically effective anti-cancer agents.

Studies on ligand-based pharmacophore modeling approach in identifying potent future EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is a validated drug target for cancer chemotherapy. Mutations in EGFR are directly linked with the development of drug resistance and this has led for the development of newer drugs in quest for more efficacious inhibitors. The current research is focused on identifying potential and safe molecules as EGFR inhibitors by using both structure and ligand based computational approaches. In quest for finding newer moieties, we have developed a pharmacophore model utilizing drugs like lazertinib, osimertinib, nazartinib, avitinib, afatininb, and talazoparib that are known to inhibit EGFR along with their downstream signaling. Ligand-based pharmacophore model have been developed to screen the ZINC database through ZINCPharmer webserver. The server has identified 9482 best possible ligands with high pharmacophoric similarity i.e., RMSD value less than 0.2 Å. The top 10 ligands with the criteria of dock score(s) and interactions were further subjected to in silico ADMET studies giving two plausible ligands that were further subjected to Molecular Dynamics and MM/PBSA free energy calculations to ensure stability to the target site. Results deduced by in silico work in the current study may be corroborated biologically in the future. The current work, therefore, provides ample opportunity for computational and medicinal chemists to work in allied areas to facilitate the design and development of novel and more efficacious EGFR inhibitors for future experimental studies.

In silico screening of therapeutic potentials from Strychnos nux-vomica against the dimeric main protease (Mpro) structure of SARS-CoV-2.

The novel coronavirus also referred to as SARS-CoV-2 causes COVID-19 and became global epidemic since its initial outbreak in Wuhan, China, in December 2019. Research efforts are still been endeavoured towards discovering/designing of potential drugs and vaccines against this virus. In the present studies, we have contributed to the development of a drug based on natural products to combat the newly emerged and life-threatening disease. The main protease (MPro) of SARS-CoV-2 is a homodimer and a key component involved in viral replication, and is considered as a prime target for anti-SARS-CoV-2 drug development. Literature survey revealed that the phytochemicals present in Strychnos nux-vomica possess several therapeutic activities. Initially, in the light of drug likeness laws, the ligand library of phytoconstituents was subjected to drug likeness analysis. The resulting compounds were taken to binding site-specific consensus-based molecular docking studies and the results were compared with the positive control drug, lopinavir, which is a main protease inhibitor. The top compounds were tested for ADME-Tox properties and antiviral activity. Further molecular dynamics simulations and MM-PBSA-based binding affinity estimation were carried out for top two lead compounds' complexes along with the apo form of main protease and positive control drug lopinavir complex, and the results were comparatively analysed. The results revealed that the two analogues of same scaffold, namely demethoxyguiaflavine and strychnoflavine, have potential against Mpro and can be validated through clinical studies.Communicated by Ramaswamy H. Sarma.

Computational study for identifying promising therapeutic agents of hydroxychloroquine analogues against SARS-CoV-2.

Hydroxychloroquine (HCQ) and its derivatives have recently gained tremendous attention as a probable medicinal agent in the COVID-19 outbreak caused by SARS-CoV-2. An efficient agent to act directly in inhibiting the SARS-CoV-2 replication is yet to be achieved. Thus, the goal is to investigate the dynamic nature of HCQ derivatives against SARS-CoV-2 main protease and spike proteins. Molecular docking studies were also performed to understand their binding affinity in silico methods using the vital protein domains and enzymes involved in replicating and multiplying SARS-CoV-2, which were the main protease and spike protein. Molecular Dynamic simulations integrated with MM-PBSA calculations have identified In silico potential inhibitors ZINC05135012 and ZINC59378113 against the main protease with -185.171 ± 16.388, -130.759 ± 15.741 kJ/mol respectively, ZINC16638693 and ZINC59378113 against spike protein -141.425 ± 22.447, -129.149 ± 11.449 kJ/mol. Identified Hit molecules had demonstrated Drug Likeliness features, PASS values and ADMET predictions with no violations. Communicated by Ramaswamy H. Sarma.

Some metal chelates with Schiff base ligand: synthesis, structure elucidation, thermal behavior, XRD evaluation, antioxidant activity, enzyme inhibition, and molecular docking studies.

Schiff bases are well-known compounds for having significant biological properties. In this study, a new Schiff base ligand and its metal complexes were synthesized, and their antioxidant and enzyme inhibitory activities were evaluated. The new Schiff base ligand was synthesized with the condensation reaction of 6-tert-butyl 3-ethyl 2-amino-4,5-dihydrothieno[2,3-c]pyridine-3,6(7H)-dicarboxylate and 2-hydroxybenzaldehyde compounds. Fe(II), Co(II), and Ni(II) metal complexes of the novel Schiff base ligand were synthesized and characterized. The purity and molecular formula of the synthesized compounds were identified with elemental analysis, infrared, ultraviolet-visible, mass spectrophotometry, powder XRD, magnetic and thermal measurements. The Schiff base acted as a three dentate chelate. The analytical and spectroscopic data suggested an octahedral geometry for the complexes. The in vitro antioxidant method studies elucidated a more effective antioxidant character of the Schiff base ligand than its metal complexes but a less effective antioxidant potential than the standard antioxidant compounds. The enzyme inhibition potentials of the synthesized compounds for AChE, BChE, and GST enzymes were determined by in vitro enzyme activity methods. The Schiff base ligand was discovered to be the best inhibitor for the AChE and BChE with the values of 7.13 ± 0.84 µM and 5.75 ± 1.03 µM Ki, respectively. Moreover, the Fe(II) complex displayed the best Ki value as 9.37 ± 1.06 µM for the GST enzyme. Finally, molecular docking studies were carried out to see the structural interactions of the compounds. The metal complexes demonstrated better binding affinities with the AChE, BChE, and GST enzymes than the Schiff base ligand. This study identified a potential Schiff base molecule against both AChE and BChE targets to further investigate for in vivo and safety evaluation.

Ligand-based design approach of potential Bcl-2 inhibitors for cancer chemotherapy.

BACKGROUND AND OBJECTIVES: Overexpression of prosurvival Bcl-2 family members make tumor cells resistant to conventional cancer therapeutic agents. It is commonly observed feature in many different types of human tumors. Hence, small-molecules as Bcl-2 inhibitors may have a promising therapeutic potential for the treatment of human cancer. The given study focusses on development of novel and small Bcl-2 inhibitors using ligand-based drug design approach. METHODS: Ligand based pharmacophore was generated using the PHASE tool of Schrödinger and screened ZINC database through ZINCPharmer webserver to identify compounds with similar features. Compounds having good fitness score were selected for molecular docking and binding interactions were compared with drugs in market as well as trials. QSAR model was generated using advanced AutoQSAR tool and validated for prediction of unknown compounds. QSAR prediction of in silico active identified three potential compounds and were subjected to investigate stability by molecular dynamics simulations and MM-PBSA binding energy calculations. RESULTS: Study identified three in silico potential molecules with good stability and binding affinity. Further substructure search and pIC50 value prediction has identified six more molecules. Total nine molecules have demonstrated good drug likeness features. CONCLUSION: Final oral rat LD50 calculation of nine molecules has identified three hit molecules i.e., ZINC76760927, ZINC76768675 and ZINC52767796 for further in vitro and in vivo testing as safe and potential Bcl-2 inhibitors.

Screening of natural compounds from Cyperus rotundus Linn against SARS-CoV-2 main protease (Mpro): An integrated computational approach.

Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that has been spreading across the globe. The World Health Organization (WHO) declared it as a public health emergency. The treatment of COVID-19 has been hampered due to the lack of effective therapeutic efforts. Main Protease (Mpro) is a key enzyme in the viral replication cycle and its non-specificity to human protease makes it a potential drug target. Cyperus rotundus Linn, which belongs to the Cyperaceae family, is a traditional herbal medicine that has been widely studied for its antiviral properties. In this study, a computational approach was used to screen natural compounds from C. rotundus Linn using BIOVIA Discovery Suite and novel potential molecules against Mpro of SARS-CoV-2 were predicted. Molecular docking was performed using LibDock protocol and selected ligands were further subjected to docking analysis by CDOCKER. The docking scores of the selected ligands were compared with standard antiretroviral drugs such as lopinavir and ritonavir to assess their binding potentials. Interaction pharmacophore analysis was then performed for the compounds exhibiting good binding scores to evaluate their protein-ligand interactions. The selected protein-ligand complexes were subjected to molecular dynamics simulation for 50 ns. Results of binding free energy analysis revealed that two compounds-ß-amyrin and stigmasta-5,22-dien-3-ol-exhibited the best binding interactions and stability. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were performed to understand the pharmacokinetic properties and safety profile of the compounds. The overall results indicate that the phytochemicals from Cyperus rotundus Linn, namely ß-amyrin and stigmasta-5,22-dien-3-ol, can be screened as potential inhibitors of SARS-CoV-2 Mpro.

Enzyme inhibitory function and phytochemical profile of Inula discoidea using in vitro and in silico methods.

Many plant species have a large diversity of secondary metabolites with different biological activities. This study aims to assess the phenolic constituent, enzyme inhibitory and antioxidant activities of the aqueous (water) and methanol extracts of Inula discoidea. The enzyme assays showed effective enzyme inhibition of the methanol extract against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), glutathione S-transferase (GST), and α-glycosidase (α-Gly) enzymes. The IC50 values for AChE, BChE, GST, and α-Gly were found as 38.5 mg/mL, 34.65 mg/mL, 77.0 mg/mL, and 40.76 mg/mL, respectively. Antioxidant properties of the aqueous and methanol extracts of I. discoidea were determined by four well-known in vitro techniques (ABTS, CUPRAC, DPPH, and FRAP methods). The antioxidant values of both water and methanol extracts were found to be better than the standard antioxidants (BHA, BHT, ascorbic acid, and α-tocopherol) in ABTS and CUPRAC methods. According to an updated LC-MS/MS technique analysis, quinic acid (21.08 mg/g), protocatechuic acid (4.49 mg/g), and gallic acid (0.48 mg/g) were found as major phenolic compounds of the plant extract. The binding interactions of major phenolic compounds of I. discoidea with the AChE, BChE, GST, and α-Gly enzymes were investigated by the molecular docking studies.

Structure-based design approach of potential BCL-2 inhibitors for cancer chemotherapy.

B-cell lymphoma 2 (BCL-2) family is one of the chief regulators of cellular apoptosis. The intricate interactions between pro-apoptotic and anti-apoptotic genes of the BCL-2 family dictate the apoptotic balance of the cell. An overexpression of the anti-apoptotic members of BCL-2 is indicative of cell death evasion and cancer metastasis. Among the four BCL-2 homology domains, the BH3 domain plays a key role in the suppression of BCL-2 expression. Therefore, BH3-mimetic drugs are currently investigated for their suitability as BCL-2 inhibitors. In the present study, we followed a structure-based pharmacophore modelling approach to identify BH3-mimetic small molecules, to formulate a more precise and targeted cancer treatment regimen. To identify proteins with similar binding features, a structure-based pharmacophore model was generated based on the structure of Bcl-2 complexed with Venetoclax (PDB-ID:6O0K). Compounds with good fitness score and pharmacophore features, screened from the ZINC database, were subjected to (i) molecular docking studies, (ii) molecular mechanics-generalized Born surface area (MM-GBSA), and (iii) absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction. From the analysis, two molecules were identified: ZINC68728276 and ZINC14166367, with docking scores of -7.323 and -8.649 kcal/mol and free binding energies (MM-GBSA) of -72.913 and -72.291 kcal/mol, respectively. The structural parameters and binding affinity of these complexes were validated through molecular dynamics simulation and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) free energy calculations and compared with Venetoclax. The results indicated stability and good binding affinity of both the compounds. The study identified ZINC68728276 and ZINC14166367 as in silico potential Bcl-2 inhibitors, which can be further considered for in vitro studies.

Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma.

Drug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inability of this drug to act on the drug resistant tumor sub-populations. Hence, in this study three novel Acridone derivative drugs AC2, AC7, and AC26 have been proposed. These molecules when combined with TMZ show major tumor cytotoxicity that is effective in suppressing growth of cancer cells in both drug sensitive and resistant sub-populations of a tumor. In this study a novel mathematical model has been developed to explore the various drug combinations that may be useful for the treatment of resistant Glioma and show that the combinations of TMZ and Acridone derivatives have a synergistic effect. Also, acute toxicity studies of all three acridone derivatives were carried out for 14 days and were found safe for oral administration of 400 mg/kg body weight on albino Wistar rats. Molecular Docking studies of acridone derivatives with P-glycoprotein (P-gp), multiple resistant protein (MRP), and O6-methylguanine-DNA methyltransferase (MGMT) revealed different binding affinities to the transporters contributing to drug resistance. It is observed that while the Acridone derivatives bind with these drug resistance causing proteins, the TMZ can produce its cytotoxicity at a much lower concentration leading to the synergistic effect. The in silico analysis corroborate well with our experimental findings using TMZ resistant (T-98) and drug sensitive (U-87) Glioma cell lines and we propose three novel drug combinations (TMZ with AC2, AC7, and AC26) and dosages that show high synergy, high selectivity and low collateral toxicity for the use in the treatment of drug resistant Glioma, which could be future drugs in the treatment of Glioblastoma.

In silico approach towards the identification of potential inhibitors from Curcuma amada Roxb against H. pylori: ADMET screening and molecular docking studies.

Introduction: The present study attempts to identify potential targets of H. pylori for novel inhibitors from therapeutic herb, mango ginger (Curcuma amada Roxb.). Methods: Crystal structure of all the selected drug targets obtained from Protein Data Bank (PDB) were subjected to molecular docking against a total of 130 compounds (found to have biological activity against H. pylori ) were retrieved from public databases. Compounds with good binding affinity were selected for Prime MM-GBSA rescoring and molecular dynamics (MD) simulation. Final list of compounds were taken for ADMET predictions. Results: Based on binding affinity denoted by glide score and ligand efficiency, mango ginger compounds were found selective to shikimate kinase and type II dehydroquinase through hydrogen bonding and salt bridge interactions. Stability of the interactions and free energy calculations by Prime MM-GBSA results confirmed the affinity of mango ginger compounds towards both shikimate kinase and type II dehydroquinase. From the above results, 15 compounds were calculated for ADMET parameters, Lipinski's rule of five, and the results were found promising without any limitations. MD simulations identified gentisic acid as hit compound for shikimate kinase of H. pylori. Conclusion: Current study could identify the in silico potential of mango ginger compounds against shikimate kinase and type II dehydroquinase targets for H. pylori infections and are suitable for in vitro and in vivo evaluation.

Transition metal complexes of a multidentate Schiff base ligand containing pyridine: synthesis, characterization, enzyme inhibitions, antioxidant properties, and molecular docking studies.

A series of Fe(II), Ni(II), and Pd(II) complexes were prepared with a novel Schiff base ligand containing pyridine moiety. The prepared compounds were characterized using FT-IR, 1H and 13 C NMR, UV-Vis, powder XRD, thermogravimetric analysis, mass spectra, magnetic susceptibility, and elemental analysis. The coordination geometry of Fe(II) and Ni(II) complexes were octahedral, where Fe(II) and Ni(II) metal ions were coordinated by an oxygen atom of the carbonyl group, a nitrogen atom of the azomethine moiety, and a phenolic oxygen atom. The Pd(II) complex had square planar geometry. All of the synthesized compounds were tested for their biochemical properties, including enzyme inhibition and antioxidant activities. According to the in vitro DPPH and FRAP antioxidant methods, the Schiff base ligand and its Fe(II)/Pd(II) complexes showed close antioxidant activities against the standards (BHA, BHT, ascorbic acid, and α-tocopherol). Enzyme inhibitions of the metal complexes were investigated against glutathione S-transferase (GST), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes. The best inhibition value (Ki) was observed for the Ni(II) complex against GST (2.63 ± 0.04 µM). Also, the Pd(II) complex showed the best inhibition value (10.17 ± 1.88 µM) against AChE. Molecular docking specified significant interactions at the active pockets of respective target enzymes. The Ni(II) complex exhibited good binding affinity against both BChE (- 9.0 kcal/mol and 9.36 ± 2.03 µM) and GST (- 7.0 kcal/mol and 2.63 ± 0.04 µM) enzymes.

In silico identification of potential inhibitors from Cinnamon against main protease and spike glycoprotein of SARS CoV-2.

Cinnamon has been utilized to remedy a lot of afflictions of humans. Literary works illustrate that it possesses numerous biological activities. Our research study is intended to recognize the phyto-derived antiviral substances from Cinnamon against COVID-19 main protease enzyme and to understand the in silico molecular basis of its activity. In the present study, 48 isolates compounds from Cinnamon retrieved from the PubMed database, are subjected to docking analysis. Docking study was performed using Autodock vina and PyRx software. Afterwards, admetSAR, as well as DruLiTo servers, were used to investigate drug-likeness prophecy. Our study shows that the nine phytochemicals of Cinnamon are very likely against the main protease enzyme of COVID-19. Further MD simulations could identify Tenufolin (TEN) and Pavetannin C1 (PAV) as hit compounds. Utilizing contemporary strategies, these phyto-compounds from a natural origin might establish a reliable medication or support lead identification. Identified hit compounds can be further taken for in vitro and in vivo studies to examine their effectiveness versus COVID-19.

Structure based pharmacophore modelling approach for the design of azaindole derivatives as DprE1 inhibitors for tuberculosis.

Cell wall of mycobacterium acts as a primary interface which helps in the regulation of important functions and also aids to pathogenicity and virulence of the organism, making it a crucial target for drug discovery. Decaprenylphosphoryl-d-ribose 2'-epimerase (DprE), is important for the growth and survival of Mycobacterium tuberculosis. DprE1 is a donor of arabinose sugars which helps in the formation of cell wall components-lipoarabinomannan and arabinogalactan through Decaprenyl-phosphoryl d-arabinose (DPA) pathway. In our study, we have chosen Azaindole derivatives as DprE1 inhibitors which possess non-covalent property. TBA7371 (azaindole derivative, non-covalent inhibitor) is currently in first phase of clinical trials as DprE1 inhibitor. Azaindoles have been found to be equally potent against drug-sensitive and isoniazid/rifampin-resistant strains. Hence, azaindoles are an attractive class for further optimization as potential DprE1 inhibitors for TB. Structure-based pharmacophore model was generated to investigate the compounds with similar molecular features. Compounds having a good fitness score and pharmacophoric features were compared with the molecules in clinical trial and were proceeded for molecular docking studies to identify the binding affinity of the compounds with target protein DprE1. Energy based calculations using Prime MM-GBSA of Schrodinger was further executed to examine free binding energy of the ligands. The prediction of pharmacokinetic parameters (ADME) plays an important role to identify safe and potent molecules which may further have potential to become drug candidates. Induced-fit docking approach and Molecular Dynamics integrated with Prime MM-GBSA calculations of both hit compounds has further confirmed the binding affinity and stability. All the results obtained from our study were interpreted and compared with DprE1 inhibitor in clinical trials. Study identified ZINC000170252277 as a potential hit compound for further biological evaluation as DprE1 inhibitor.