Screening of bioactive compounds from selected mushroom species against putative drug targets in Mycobacterium tuberculosis: a multi-target approach.

Mycobacterium tuberculosis (Mtb) is a notorious pathogen that causes one of the highest mortalities globally. Due to a pressing demand to identify novel therapeutic alternatives, the present study aims to focus on screening the putative drug targets and prioritizing their role in antibacterial drug development. The most vital proteins involved in the Biotin biosynthesis pathway and the Lipoarabinomannan (LAM) pathway such as biotin synthase (bioB) and alpha-(1->6)-mannopyranosyltransferase A (mptA) respectively, along with other essential virulence proteins of Mtb were selected as drug targets. Among these, the ones without native structures were modelled and validated using standard bioinformatics tools. Further, the interactions were performed with naturally available lead molecules present in selected mushroom species such as Agaricus bisporus, Pleurotus djamor, Hypsizygus ulmarius. Through Gas Chromatography-Mass Spectrometry (GC-MS), 15 bioactive compounds from the methanolic extract of mushrooms were identified. Further, 4 were selected based on drug-likeness and pharmacokinetic screening for molecular docking analysis against our prioritized targets wherein Benz[e]azulene from Pleurotus djamor illustrated a good binding affinity with a LF rank score of -9.036 kcal mol -1 against nuoM (NADH quinone oxidoreductase subunit M) and could be used as a prospective candidate in order to combat Tuberculosis (TB). Furthermore, the stability of the complex are validated using MD Simulations and subsequently, the binding free energy was calculated using MM-GBSA analysis. Thus, the current in silico analysis suggests a promising role of compounds extracted from mushrooms in tackling the TB burden.Communicated by Ramaswamy H. Sarma.

Novel pyrimidines as COX-2 selective inhibitors: synthesis, DFT analysis, molecular docking and dynamic simulation studies.

Pyrimidine and its derivatives are associated with varieties of biological properties. Therefore, we herein reported the synthesis of four novel pyrimidines (2, 3, and 4a, b) derivatives. The structure of these molecules is confirmed by spectroscopic methods such as IR, NMR, and Mass analysis. The electronic behavior of synthesized compounds 4a, b and in silico drug design 4 c, d was explained by Density Functional Theory estimations at the DFT/B3LYP level via 6-31 G++ (d, p) replicates the structure and geometry. All the synthesized compounds were screened for their in vitro COX-1 and COX-2 inhibitory activity compared to standards Celecoxib and Ibuprofen. Compounds 3 and 4a afforded excellent COX-1 and COX-2 inhibitory activities at IC50 = 5.50 and 5.05 µM against COX-1, 0.85 and 0.65 µM against COX-2, respectively. The standard drugs Celecoxib and Ibuprofen showed inhibitory activity at IC50 = 6.34 and 3.1 µM against COX-1, 0.56 and 1.2 µM against COX-2, respectively. Further, these compounds showed high potential docking with SARS-CoV-2 Omicron protease & COX-2 and predicted drug-likeness for the pyrimidine analogs by using Molinspiration. The protein stability, fluctuations of APO-protein, protein-ligand complexes were investigated through Molecular Dynamics simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified.Communicated by Ramaswamy H. Sarma.

VinaLigGen: a method to generate LigPlots and retrieval of hydrogen and hydrophobic interactions from protein-ligand complexes.

Developments in the field of computational structural biology and with increasing computing speeds have encouraged researchers in studying large compound libraries during the virtual screening. After performing molecular docking, the consideration of vina score in filtering the compounds without collecting the hydrogen bond or hydrophobic interaction between protein and ligand complex leads to missing multiple good lead molecules. The tools used for virtual screening in drug design and discovery studies were previously designed and developed for small datasets. LigPlots were used to generate 2-dimensional (2D) interaction maps of protein-ligand complexes. These maps depict diverse bonds like hydrogen and hydrophobic interactions in varied colors for all ligand conformations within the library. However, handling large numbers of protein-ligand complexes can make this process quite laborious. The development of a tool is strongly required or an implementation of automation to generate all the interaction details has a strong demand. This paper describes an implementation of an automation technique on the executable programs like ligplot.exe, hbplus.exe and hbadd.exe to obtain the 2D interaction map (LigPlots) of the protein and ligand complex (*.ps) and hydrogen bonds and hydrophobic interactions in *.csv format for molecules to be considered for virtual screening by using some sorting & searching algorithms and python's file handling functions, and it also mentions the program's limitations and availability of the program. The program can be found on github.Communicated by Ramaswamy H. Sarma.

Reverse vaccinology & immunoinformatics approach to design a multiepitope vaccine (CV3Ag-antiMRSA) against methicillin resistant Staphylococcus aureus (MRSA) - a pathogen affecting both human and animal health.

Infections caused by drug resistant bacteria is a silent detrimental pandemic affecting the global health care profoundly. Methicillin resistant Staphylococcus aureus (MRSA) is a pathogen that causes serious infections in different settings (community, hospital & veterinary) whose treatment remains highly challenging due to its powerful characteristics (antibiotic resistance strategies, virulence factors). In this study, we used reverse vaccinology (RV) approach and designed an immunogenic multi epitope vaccine (CV3Ag-antiMRSA) targeting three potential antigen candidates viz., mecA encoding transpeptidase (PBP2a) protein responsible for conferring methicillin resistance and two virulence determinants - hlgA encoding gamma-hemolysin component A (a pore forming toxin) and isdB encoding iron regulated surface determinant B (heme transport component that allows S. aureus to scavenge iron from host hemoglobin and myoglobin). We employed an array of immunoinformatic tools/server to identify and use immunogenic epitopes (B cell and MHC class) to develop the chimeric subunit vaccine V4 (CV3Ag-antiMRSA) with immune modulating adjuvant and linkers. Based on different parameters, the vaccine construct V4 (CV3Ag-antiMRSA) was determined to be suitable vaccine (antigenic and non-allergen). Molecular docking and simulation of CV3Ag-antiMRSA with Toll Like Receptor (TLR2) predicted its immuno-stimulating potential. Finally, in silico cloning of CV3Ag-antiMRSA construct into pet28a and pet30 vector displayed its feasibility for the heterologous expression in the E. coli expression system. This vaccine candidate (CV3Ag-antiMRSA) designed based on the MRSA genomes obtained from both animal and human hosts can be experimentally validated and thereby contribute to vaccine development to impart protection to both animal and human health.Communicated by Ramaswamy H. Sarma.

Spectroscopic, theoretical and computational investigations of novel benzo[b]thiophene based ligand and its M(II) complexes: As high portentous antimicrobial and antioxidant agents.

The reaction of 3-chlorobenzo[b]thiophene-2-carbohydrazide with 4-(diethylamino) salicylaldehyde gave the new ligand; 3-chloro-N'-(4-(diethylamino)-2-hydroxybenzylidene)-benzo[b]thiophene-2-carbohydrazide. The Cu(II), Co(II), Ni(II), and Zn(II) complexes have been successfully prepared. The ligand and the complexes were characterized by analytical, FT-IR, 1H NMR, mass, UV-visible spectroscopy, molar conductivity, and magnetic susceptibility measurements. The FT-IR spectral data showed that the ligand adopted a tridentate fashion when binding with the metal ions via the nitrogen atoms of the imine (C = N), carboxyl (C = O), and phenolic oxygen (O-H) donor atoms. Density Functional Theory (DFT) estimations for the ligand at the DFT/B3LYP level via 6-31G++ (d, p) replicate the structure and geometry. Finally, HOMO and LUMO analyses were used for the charge transfer interface of the structure. Furthermore, molecular docking and ADME calculations were also performed to correlate and interpret the experimental results. The antimicrobial activity study illustrated enhancement in the activity of the free ligand upon complex formation, and the Cu(II) complex (MIC 25 µg mL-1) may be considered a promising antibacterial agent, and the Ni(II) and Zn(II) complexes (MIC 25 µg mL-1) as promising antifungal agents. Also, synthesized Cu(II) and Zn(II) metal complexes (MIC 3.125 µg mL-1) showed promising anti-TB activity against M. tuberculosis. Further, benzo[b]thiophene-based ligand and its metal complexes were evaluated for in vitro antioxidant activity, and in silico docking studies were carried out against Cytochrome c Peroxidase (PDB ID: 2X08).

Design, synthesis, computational molecular docking studies of novel heterocyclics bearing 1,2,4-triazole, 1,3,4-oxadiazole conjugates as potent antibacterial and antitubercular agents.

Herein, we report the synthesis, and characterization of a new series of 1,3,4-oxadiazole and 1,2,4-triazole derivatives based on azaindole acetamides and assigned as potential antibacterial and antitubercular substances. The structures of these compounds were established by 1H NMR, 13C NMR, and HRMS spectral analysis. In preliminary antibacterial studies, analogues 6b, 6d, and 6e were found to be most effective against S. aureus with MIC of 12.5, 6.25, and 12.5 µg/mL, whereas 8d displayed excellent activity against S. aureus, B. subtilis, E. coli bacterial strains with zones of inhibition 12.5, 25, and 12.5 µg/mL respectively. Particularly, the prepared scaffolds 8c, 8d, and 8e showed remarkable antifungal activity with MIC value 12.5, 12.5, and 6.25 µg/mL against A. flavus and 6d, 6c producing an increase in the activity against C. Albicans with zones of inhibition 12.5 and 12.5 µg/mL respectively. Also, through the antitubercular studies, we found that compounds 6e and 8b have a strong activity with M. tuberculosis H37Rv with MICs 3.26, and 6.48 µg/mL, respectively. The protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3, and potential lead molecules were identified. Our findings were further confirmed using molecular docking, revealing that azaindole based ligand 6e, 6f, and 8a has strong hydrophobic Tyr179, Trp183, Ile177, Ile445, and H-bondings interactions Arg151 and Arg454 through molecular dynamics simulation studies, making it potential biological compound. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.Communicated by Ramaswamy H. Sarma.

Exploration of Indolo[3,2c]isoquinoline derived triazoles as potential antimicrobial and DNA cleavage agents: Synthesis, DFT calculations, and molecular modeling studies.

Indole and its derivatives are well-known assorted motif in drug design and development. We here in reporting synthesis of new 9-chloro-1-(4-substituted phenyl)-12H-indolo[2,3-c][1,2,4]triazolo[3,4-a]isoquinolines 7 (a-h). Structures of the newly synthesized compounds were confirmed by making use of spectroscopic techniques like IR, NMR and Mass. The DFT calculations were taken for the selected molecules using CAM-B3LYP hybrid functional with a 6-31 + g(d) all-electron basis set using the Gaussian 09 package. The drug-likeness predictions were described for the synthesized derivatives. The In vitro antimicrobial and DNA cleavage activities were reported for all compounds 7 (a-h). The compounds 7a, 7b, and 7h showed excellent microbial inhibition and DNA cleavage activity as compared to standard drugs. Furthermore, the docking studies for the newly synthesized molecules were carried out by Auto dock software with two molecular targets Epidermal Growth Factor Receptor tyrosine kinase (1 M17) and C-kit Tyrosine Kinase (1 T46) exhibited better binding affinity of all synthesized compounds. In addition, the docking results were observed to be in full agreement with the in vitro DNA cleavage assay suggesting the potential of synthesized metal complexes in biological applications. Lastly, the protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified.

Investigation of embelin synthetic hybrids as potential COVID-19 and COX inhibitors: Synthesis, spectral analysis, DFT calculations and molecular docking studies.

Embelin (2, 5-dihydroxy-3-undecyl-1,4-benzoquinone), a benzoquinone isolated from fruits of Embelia ribes has miscellaneous biological potentials including; anticancer, anti-inflammation, antibiotic, and anti-hyperglycemic activities. Also, embelin down-regulates the overexpression of inflammatory pathways like NF-kB, TACE, TNF-α, and other cytokines. Furthermore, embelin fascinated synthetic interest as a pharmacologically active compound. The present article involves the design, synthesis, DFT calculations, and molecular docking studies of embelin derivatives as cyclooxygenase inhibitors of embelin derivatives. The structure of these derivatives is confirmed by the various spectral analyses such as IR, NMR, and Mass. The DFT calculations were carried out for the molecules (1-8) using CAM-B3LYP hybrid functional with a 6-31+g(d) all-electron basis set using the Gaussian 09 package. Second-order harmonic vibrational calculations are used to check the minimum nature of the geometry. Further, HOMO and LUMO analyses were used for the charge transfer interface between the structures. Based on our previous work and structural activity relationship study, foresaid embelin derivatives were evaluated for in vitro COX-1 and COX-2 inhibitory activity. The compounds 3, 4, 7, and 8 demonstrated excellent COX inhibitions with IC50 values of 1.65, 1.54, 1.56, and 1.23 µM compared to standard drugs Celecoxib and Ibuprofen. Finally, the molecular docking studies carried out with Covid-19 and cyclooxygenase with all the newly synthesized embelin derivatives.

Molecular docking and dynamic simulation to identify potential phytocompound inhibitors for EGFR and HER2 as anti-breast cancer agents.

Breast cancer is the most prevalent cancer in women worldwide. To treat human breast cancer by inhibiting EGFR and HER2 targets is an important therapeutic option. Phytochemicals are found to have beneficial health effects in treating various diseases. An effort has been made to virtually screen phytochemical inhibitor by molecular docking and dynamic simulation in the current studies. The docking scores analysis resulted in a common hit Panaxadiol ligand with a low dock score for EGFR and HER2 targets. The inhibitory action of the phytocompounds was also validated by comparing it with the reference compounds Erlotinib for EGFR and Neratinib for HER2. Molecular dynamic simulation of EGFR and HER2 lead complexes ensure the ligand's appropriate refinement in the dynamic system. The target and ligand complex interaction motif established a high affinity of lead candidates in a dynamic system similar to molecular docking results. This study reveals that Panaxadiol hit molecule can be developed as a novel multi-target EGFR and HER2 target inhibitor with greater potential and low toxicity.Communicated by Ramaswamy H. Sarma.

In silico modelling and virtual screening for identification of inhibitors for spore wall protein-5 in Nosema bombycis.

Bombyx mori is an insect of economic importance in the production of silk. It often gets infected by Nosema bombycis, an intracellular parasite. The infection causes a fatal disease known as a Pebrine which affects the development of the worm. The infected larvae of silkworms are coated with brown spots and are unable to spin the silkworm thread. They lose appetite, become sluggish, opaque and ultimately die. The Spore Wall Protein 5 is an exospore protein in N. bombycis and interacts with the polar tube proteins PTP2 and PTP3, a part of the extrusion apparatus that facilitates infection of the host. SWP5 also plays an essential part in maintaining the structural integrity of the spore wall and could possibly regulate the route of the infection in N. bombycis. In the present study, the homology modelling of three protein structures SWP5, PTP2 and PTP3 were performed. The protein-protein interaction was studied and a complete complex of SWP5, PTP2 and PTP3 was generated to understand the discharge of the penetrating polar tube. Virtual screening and molecular dynamics simulation was performed and a potential lead-like molecule is identified.Communicated by Ramaswamy H. Sarma.

Activation of Microbiota Sensing - Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-ß Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis.

Multiple emerging evidence indicates that the gut microbiota contributes to the pathology of Alzheimer's disease (AD)-a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated, and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from short chain fatty acids (SCFAs) produced by microbiota. The abundance of SCFAs, is often low in the gut of older adults with AD. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aß) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists using an in-silico library of more than 144,000 natural compounds and selected 15 of them based on binding with FFAR2-agonist active sites. Fenchol (a natural compound commonly present in basil) was recognized as a potential FFAR2 stimulator in neuronal cells and demonstrated protective effects against Aß-stimulated neurodegeneration in an FFAR2-dependent manner. In addition, Fenchol reduced AD-like phenotypes, such as Aß-accumulation, and impaired chemotaxis behavior in Caenorhabditis (C.) elegans and mice models, by increasing Aß-clearance via the promotion of proteolysis and reduced senescence in neuronal cells. These results suggest that the inhibition of FFAR2 signaling promotes Aß-induced neurodegeneration, while the activation of FFAR2 by Fenchol ameliorates these abnormalities by promoting proteolytic Aß-clearance and reducing cellular senescence. Thus, stimulation of FFAR2 signaling by Fenchol as a natural compound can be a therapeutic approach to ameliorate AD pathology.

Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View.

The role of the gut microbiome in human health is becoming apparent. The major functional impact of the gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment or are absorbed into circulation to impact distant cells/organs. Short-chain fatty acids (SCFAs) are the major microbial metabolites that are produced in the gut through the fermentation of non-digestible fibers. SCFAs are known to function through various mechanisms, however, their signaling through free fatty acid receptors 2 and 3 (FFAR2/3; type of G-coupled protein receptors) is a new therapeutic approach. FFAR2/3 are widely expressed in diverse cell types in human and mice, and function as sensors of SCFAs to change several physiological and cellular functions. FFAR2/3 modulate neurological signaling, energy metabolism, intestinal cellular homeostasis, immune response, and hormone synthesis. FFAR2/3 function through Gi and/or Gq signaling, that is mediated through specific structural features of SCFAs-FFAR2/3 bindings and modulating specific signaling pathway. In this review, we discuss the wide-spread expression and structural homologies between human and mice FFAR2/3, and their role in different human health conditions. This information can unlock opportunities to weigh the potential of FFAR2/3 as a drug target to prevent human diseases.

Homology modeling, virtual screening and dynamics study of proteins involved in Pebrine - Serine protease inhibitor 106 and spore wall protein 26.

Pebrine is a microsporidian disease caused by Nosema bombycis in Bombyx mori (silk worm) which results in brown/black spots. The affected larvae either spin cocoons which are flimsy with low silk content or not spin a cocoon. It has been hypothesised that Serine Protease Inhibitor 106 (SPN106) is responsible for evasion of host immune system by inhibiting the melanization process in silkworms. Also, Spore Wall Protein 26 (SWP26) has been observed to bind with Ig- like protein Bombyx mori turtle-like protein (Bm-TLP) facilitating the attachment of the microsporidian to the host and contributing to infectivity. Till date, there is no crystal structure of the proteins SPN106, SWP26 and Bm-TLP available. In this study, we performed homology modeling of the three structures using Modeller v9.18 and the binding pockets were identified. Virtual screening was conducted using AutoDock Vina on a ligand library consisting of 28,870 lead-like molecules. The protein stability, compactness, fluctuations and protein-ligand interactions were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3 and a potential lead molecule was identified.Communicated by Ramaswamy H. Sarma.

In silico antitubercular activity analysis of benzofuran and naphthofuran derivatives.

For the human health, Mycobacterium tuberculosis (MTB) is the deadliest enemy since decades due to its multidrug resistant strains. During latent stage of tuberculosis infection, MTB consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence. NarL is a nitrate/nitrite response transcriptional regulatory protein of two-component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Using in silico approach, the molecular docking of benzofuran and naphthofuran derivatives and dynamic study of benzofuran derivative were performed. It was observed that compound Ethyl 5-bromo-3-ethoxycarbonylamino-1-benzofuran-2-carboxylate could be stabilized at the active site for over 10 ns of simulation. Here we suggest that derivatives of benzofuran moiety can lead to developing novel antituberculosis drugs.

Inhibition of NarL of Mycobacterium Tuberculosis: an in silico approach.

Mycobacterium tuberculosis (MTB) consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence during latent stage of tuberculosis infection. NarL is a nitrate/nitrite response transcriptional regulatory protein of two-component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Virtual screening was performed using Autodock suite for the compounds from ZINC database against NarL and potential inhibitors was identified to inhibit the activation of NarL by affecting its phosphorylation. Molecular dynamics simulation studies predicted the stability of 1-{1-[(3-nitrophenyl) methyl] piperidin-2-yl} ethan-1-amine in the active site of NarL over 10 ns simulation. Phosphorylation of NarL by small molecule phospho-donors is also investigated in the present study. Here we suggest that nitro benzene - amine piperidine moiety can be an effective lead candidate for developing novel anti-tuberculosis drugs.

Chemogenomics profiling of drug targets of peptidoglycan biosynthesis pathway in Leptospira interrogans by virtual screening approaches.

Leptospirosis is a worldwide zoonosis of global concern caused by Leptospira interrogans. The availability of ligand libraries has facilitated the search for novel drug targets using chemogenomics approaches, compared with the traditional method of drug discovery, which is time consuming and yields few leads with little intracellular information for guiding target selection. Recent subtractive genomics studies have revealed the putative drug targets in peptidoglycan biosynthesis pathways in Leptospira interrogans. Aligand library for the murD ligase enzyme in the peptidoglycan pathway has also been identified. Our approach in this research involves screening of the pre-existing ligand library of murD with related protein family members in the putative drug target assembly in the peptidoglycan biosynthesis pathway. A chemogenomics approach has been implemented here, which involves screening of known ligands of a protein family having analogous domain architecture for identification of leads for existing druggable protein family members. By means of this approach, one murC and one murF inhibitor were identified, providing a platform for developing an antileptospirosis drug targeting the peptidoglycan biosynthesis pathway. Given that the peptidoglycan biosynthesis pathway is exclusive to bacteria, the in silico identified mur ligase inhibitors are expected to be broad-spectrum Gram-negative inhibitors if synthesized and tested in in vitro and in vivo assays.

Ethyl 5-bromo-3-eth-oxy-carbonyl-amino-1-benzofuran-2-carboxyl-ate.

In the title compound, C14H14BrNO5, the ester group is disordered [occupancy ratio 0.52 (2):0.48 (2)]. The major component is nearly coplanar with the benzofuran plane, subtending a dihedral angle of 7.84 (2)°, while the amide group is twisted out of the benzofuran plane making a dihedral angle of 39.69 (2)°. An intra-molecular N-H⋯O hydrogen bond occurs. In the crystal, pairs of weak C-H⋯O hydrogen bonds link the mol-ecules into inversion dimers, which are further linked via strong N-H⋯O hydrogen bonds, generating a zigzag chain extending along [100].

The sensor region of the ubiquitous cytosolic sensor kinase, PdtaS, contains PAS and GAF domain sensing modules.

Two-component systems, a sensor histidine kinase (HK) and a response regulator (RR), are ubiquitous signaling systems that allow prokaryotes to respond to external challenges. HKs normally have sensing modules and highly conserved cytosolic histidine kinase and ATPase domains. The interaction between the activated phosphohistidine and the cognate RR allows an external signal to be passed from the exterior of gram-positive bacteria (GPB) to the cytoplasm. Orthologs of the PdtaS/PdtaR regulatory system, found in most GPB phyla, are unusual in two respects. The HK is not membrane anchored, and the RR acts at the level of transcriptional antitermination. The structure of the complete sensor region of the cytosolic HK, PdtaS, from Mycobacterium tuberculosis consists of closely linked GAF and PAS domains. The structure and sequence analysis suggest that the PdtaS/PdtaR regulatory system is structurally equivalent to the EutW/EutV system regulating ethanolamine catabolism in some phyla but that the effector for the PAS domain is not ethanolamine in the Actinobacteria.

Comparative reverse screening approach to identify potential anti-neoplastic targets of saffron functional components and binding mode.

BACKGROUND: In the last two decades, pioneering research on anti-tumour activity of saffron has shed light on the role of crocetin, picrocrocin and safranal, as broad spectrum anti-neoplastic agents. However, the exact mechanisms have yet to be elucidated. Identification and characterization of the targets of bioactive constituents will play an imperative role in demystifying the complex anti-neoplastic machinery. METHODS: In the quest of potential target identification, a dual virtual screening approach utilizing two inverse screening systems, one predicated on idTarget and the other on PharmMapper was here employed. A set of target proteins associated with multiple forms of cancer and ranked by Fit Score and Binding energy were obtained from the two independent inverse screening platforms. The validity of the results was checked by meticulously analyzing the post-docking binding pose of the picrocrocin with Hsp90 alpha in AutoDock. RESULTS: The docking pose reveals that electrostatic and hydrogen bonds play the key role in inter-molecular interactions in ligand binding. Picrocrocin binds to the Hsp90 alpha with a definite orientation appropriate for nucleophilic attacks by several electrical residues inside the Hsp90-alpha ATPase catalytic site. CONCLUSION: This study reveals functional information about the anti-tumor mechanism of saffron bioactive constituents. Also, a tractable set of anti-neoplastic targets for saffron has been generated in this study which can be further authenticated by in vivo and in vitro experiments.

Molecular interaction of fenvalarate with actin.

The structure of α-Cyano-3-phenoxybenzyl-2-(4-chlorophenyl)-3-methylbutyrate (Fenvalarate) has been established by X-ray crystallography to understand the structure-activity relationship, which is of paramount importance in the toxicological studies of the compound. Fenvalarate is stabilized by intermolecular C-H…O, C-H…Cl, C-H…π and C-H…N interactions which are responsible for the stability of the compound and its interaction with the Actin. The crystallographic coordinates of the compound was extrapolated to docking studies to elucidate the action of fenvalarate against neural cytoskeletal protein of insect and mammalian ß-actin. A strong affinity was observed in binding of fenvalarate with insect ß-actin (-7.71kcal/mol, Ki = 2.23µM) indicating it as a potent insecticide and moderate toxicity towards mammalian ß-actin (-7.07kcal/mol, Ki=6.54µM).