Exploring oral drug delivery: In vitro release and mathematical modeling of hydrophobic drug (Na-L-thyroxine) and its cyclodextrin inclusion complex in chitosan microparticles.

Na-l-Thyroxine (Na-l-Thy) is a frequently prescribed synthetic hormone for hypothyroidism treatment. Despite its efficacy, its hydrophobic nature poses a challenge for achieving optimal bioavailability. To address this, researchers explored various delivery methods, including micro-formulations and nano-formulations, for precise and prolonged release of hydrophobic and hydrophilic drugs. In this study, we developed micro-formulations with cyclodextrin and chitosan. Docking studies identified γ-cyclodextrin as the preferred option for forming a stable complex with Na-l-Thyroxine compared to α, and ß-cyclodextrins. Two micro-formulations were prepared compared: Na-l-Thyroxine loaded on chitosan (CS + Na-l-Thy) and Na-l-Thyroxine and γ-cyclodextrin inclusion complex (IC) loaded on chitosan (CS + IC). CS + IC exhibited superior encapsulation efficiency (91.25 %) and loading capacity (18.62 %) compared to CS + Na-l-Thy (encapsulation efficiency: 70.24 %, loading capacity: 21.18 %). Characterization using FTIR, SEM, and TGA validated successful encapsulation of Na-l-Thy in spherical microparticles with high thermal stability. In-vitro release studies at pH 1.2 and 7.4 showed that the CS + IC microparticles displayed gradual, consistent drug release compared to CS + Na-l-Thy -Thy. Both formulations showed faster release at pH 1.2 than at pH 7.4. Reaction kinetics analysis of release studies of CS + Na-l-Thy and CS + IC were best described by Higuchi kinetic model and Korsemeyer-Peppas kinetic model respectively. This study suggests that the CS + IC microparticles are an effective and stable delivery system for sustained release of hydrophobic Na-l-Thy.

Smartphone-based diagnostics for biosensing infectious human pathogens.

The widespread usage of smartphones has made accessing vast troves of data easier for everyone. Smartphones are powerful, handy, and easy to operate, making them a valuable tool for improving public health through diagnostics. When combined with other devices and sensors, smartphones have shown potential for detecting, visualizing, collecting, and transferring data, enabling rapid disease diagnosis. In resource-limited settings, the user-friendly operating system of smartphones allows them to function as a point-of-care platform for healthcare and disease diagnosis. Herein, we critically reviewed the smartphone-based biosensors for the diagnosis and detection of diseases caused by infectious human pathogens, such as deadly viruses, bacteria, and fungi. These biosensors use several analytical sensing methods, including microscopic imaging, instrumental interface, colorimetric, fluorescence, and electrochemical biosensors. We have discussed the diverse diagnosis strategies and analytical performances of smartphone-based detection systems in identifying infectious human pathogens, along with future perspectives.

Role of Estradiol Hormone in Human Life and Electrochemical Aptasensing of 17ß-Estradiol: A Review.

Estradiol is known as one of the most potent estrogenic endocrine-disrupting chemicals (EDCs) that may cause various health implications on human growth, metabolism regulation, the reproduction system, and possibly cancers. The detection of these EDCs in our surroundings, such as in foods and beverages, is important to prevent such harmful effects on humans. Aptamers are a promising class of bio-receptors for estradiol detection due to their chemical stability and high affinity. With the development of aptamer technology, electrochemical aptasensing became an important tool for estradiol detection. This review provides detailed information on various technological interventions in electrochemical estradiol detection in solutions and categorized the aptasensing mechanisms, aptamer immobilization strategies, and electrode materials. Moreover, we also discussed the role of estradiol in human physiology and signaling mechanisms. The level of estradiol in circulation is associated with normal and diseased conditions. The aptamer-based electrochemical sensing techniques are powerful and sensitive for estradiol detection.

A Promising Review on Cyclodextrin Conjugated Paclitaxel Nanoparticles for Cancer Treatment.

This review presented the unique characteristics of different types of cyclodextrin polymers by non-covalent host-guest interactions to synthesize an inclusion complex. Various cancers are treated with different types of modified cyclodextrins, along with the anticancer drug paclitaxel. PTX acts as a mitotic inhibitor, but due to its low dissolution and permeability in aqueous solutions, it causes considerable challenges for drug delivery system (DDS) designs. To enhance the solubility, it is reformulated with derivatives of cyclodextrins using freeze-drying and co-solvent lyophilization methods. The present supramolecular assemblies involve cyclodextrin as a key mediator, which is encapsulated with paclitaxel and their controlled release at the targeted area is highlighted using different DDS. In addition, the application of cyclodextrins in cancer treatment, which reduces the off-target effects, is briefly demonstrated using various types of cancer cell lines. A new nano-formulation of PTX is used to improve the antitumor activity compared to normal PTX DDS in lungs and breast cancer is well defined in the present review.

Genome-wide lone strand adenine methylation in Deinococcus radiodurans R1: Regulation of gene expression through DR0643-dependent adenine methylation.

DNA methylation is a covalent modification of adenine or cytosine in the genome of an organism and is found in diverse microbes including the radiation resistant bacterium Deinococcus radiodurans R1. Although earlier findings have confirmed repression or de-repression of certain genes in adenine methyltransferase (DR_0643/Dam1DR) deficient D. radiodurans mutant however, the overall regulatory aspects of Dam1DR-mediated adenine methylation remain mostly unexplored. In the present study, we compared the genome-wide methylome and the corresponding transcriptome of D. radiodurans WT and Δdam1 mutant to explore the correlation between methylation and gene expression. In D. radiodurans, deletion of DR_0643 ORF (Δdam1) led to hypomethylation of 512 genes resulting in differential expression of 168 genes (99 genes are upregulated and 69 genes are downregulated). The modification patterns deduced for Dam1DR (DR_0643) and Dam2DR (DR_2267) were non-palindromic and atypical. Moreover, we observed methylation at opportunistic sites that show adenine methylation only in D. radiodurans Δdam1 and not in D. radiodurans WT. Correlation between the methylome and transcriptome suggests that hypomethylation at Dam1DR specific sites had both negative as well as a positive effects on gene expression. Pathways such as amino acid metabolism, transport, oxidative phosphorylation, quorum sensing, signal transduction, two-component system, glycolysis/gluconeogenesis, TCA cycle, glyoxylate and dicarboxylate metabolism were modulated by Dam1DR-mediated adenine methylation in D. radiodurans. Processes such as DNA repair, recombination, ATPase and transmembrane transporter activity were enriched when Dam1DR mutant was subjected to radiation stress. We further evaluated the molecular interactions and mode of binding between Dam1DR protein and S-adenosyl methionine using molecular docking followed by MD simulation. To get a better insight into the methylation mechanism, the Dam1DR-SAM complex was also docked with a DNA molecule to elucidate DNA-Dam1DR structural interaction during methyl-group transfer reaction. In summary, our work presents comprehensive and integrative approaches to investigate both functional and structural aspects of DNA adenine methyltransferase (Dam1DR) in D. radiodurans biology.

Identification and characterization of novel RdRp and Nsp15 inhibitors for SARS-COV2 using computational approach.

The World Health Organization has declared COVID-19 as a global health emergency. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and highlights an urgent need for therapeutics. Here, we have employed a series of computer-aided drug repurposing campaign to discover inhibitors of RNA dependent RNA polymerase (RdRp) and Nsp15/EndoU. Subsequently, MD simulation has been performed to observe dynamic behavior of identified leads at the active site of RdRp and Nsp15. We successfully identified novel lead molecule such as Alectinib for RdRp while Naldemedine and Ergotamine for NSP15. These lead molecules were accommodated in the active site of the enzyme and stabilized by the networks of the hydrogen bond, pi type and hydrophobic interaction with key residues of either target. Interestingly, identified compounds show molecular mimicry in terms of molecular interactions with key residues of RdRp and Nsp15 essential for catalysis and substrate interaction. Previously, Alectinib, Naldemedine and Ergotamine were used as drug in different diseases might be repurposed against selected protein targets of COVID19. Finally, we propose that the identified inhibitors represent a novel lead molecule to design a more effective inhibitor to stop the progress of pathogen.Communicated by Ramaswamy H. Sarma.

Known compounds and new lessons: structural and electronic basis of flavonoid-based bioactivities.

Flavonoids correspond to a major class of polyphenolic phytochemicals with flavone as major parent scaffold. This class of compounds is attributed with very rich nutritional as well as therapeutic values. The present study focuses on a panel of 16 flavonoid molecules that are demonstrated to exhibit various bioactivities like anti-angiogenic, anti-inflammatory as well as possess antioxidant potential. The electronic basis of these bioactivities is rarely explored, and structural basis of flavonoid-induced cyclooxygenase (COX) inhibition has still remained an uncharted area. The current report thus focuses on providing an electronic explanation of these bioactivities using density functional theory-based quantum chemical descriptors. We also attempt to provide a structure-activity relation model for COX by inhibition of these 16 flavonoids using molecular docking. Here, we report molecular dynamics data from 16 flavonoid-COX-2 complexes performed for 50 nanoseconds each that demonstrates key structural and dynamic aspects of flavonoid-based COX inhibition in light of observed experimental facts. Interaction analysis and evaluation of side-chain dynamics presented in current study are well in agreement with the empirical study and is hoped to pave new avenues towards design and development of COX-2 selective chemical agents. Abbreviations2'HFN-2'hydroxy flavonone2D2 dimension3D3 dimension3H7MF3-hydroxy-7-methoxy flavone4'HFN-4'hydroxy flavonone4'MF- 4'methoxy flavone7HFN7-hydroxy flavononeCHARMMChemistry at Harvard Macromolecular MechanicsCOXcyclooxygenaseCOX-1cyclooxygenase-1COX-2cyclooxygenase-2DMdipole momentDPPH- 2, 2diphenyl-1-picryl hydrazineEAelectron affinitiesEGFRepidermal growth factor receptorE-HOMOHighest occupied molecular orbital energyE-LUMOLowest unoccupied molecular orbital energyEPAeicosapentaenoic acidFROG2FRee Online druG conformation generationGAGenetic AlgorithmGROMACSGROningen MAchine for Chemical SimulationsHOMOHighest occupied molecular orbitalIPIonization potentialLOMOLowest unoccupied molecular orbitalMDMolecular dynamicsMOMolecular orbitalNAMDNanoscale Molecular DynamicsNSAIDsNon-Steroidal Anti Inflammatory DrugsNsnanosecondsNVEEnsemble-constant-energy, constant-volume, Constant particle ensemblePDB-IDProtein Data Bank IdentifierPMEParticle Mesh EwaldPyRXPython PrescriptionRMSDRoot-Mean-Square DeviationRMSFRoot-Mean-Square FluctuationRLSreactive lipid speciesROSReactive Oxygen SpeciesSASAsolvent accessible surface areaSMILESsimplified molecular-input line-entry systemSORsuperoxide anion radicalUFFUniversal force fieldVEGFvascular endothelial growth factorVEGFRvascular endothelial growth factor receptorVMDVisual molecular dynamicsCommunicated by Ramaswamy H. Sarma.

Azadirachtin-A from Azadirachta indica Impacts Multiple Biological Targets in Cotton Bollworm Helicoverpa armigera.

Azadirachtin-A (AzaA) from the Indian neem tree (Azadirachta indica) has insecticidal properties; however, its molecular mechanism remains elusive. The "targeted and nontargeted proteomic profiling", metabolomics, matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) imaging, gene expression, and in silico analysis provided clues about its action on Helicoverpa armigera. Fourth instar H. armigera larvae fed on AzaA-based diet (AzaD) suffered from significant mortality, growth retardation, reduced larval mass, complications in molting, and prolonged development. Furthermore, death of AzaD-fed larvae was observed with various phenotypes like bursting, blackening, and half-molting. Liquid chromatography-mass spectrometry (LC-MS) data showed limited catabolic processing of ingested AzaA and dramatic alternations of primary metabolism in H. armigera. MALDI-TOF imaging indicated the presence of AzaA in midgut of H. armigera. In the gut, out of 79 proteins identified, 34 were upregulated, which were related to digestion, immunity, energy production, and apoptosis mechanism. On the other hand, 45 proteins were downregulated, including those from carbohydrate metabolism, lipid metabolism, and energy transfer. In the hemolymph, 21 upregulated proteins were reported to be involved in immunity, RNA processing, and mRNA-directed protein synthesis, while 7 downregulated proteins were implicated in energy transfer, hydrolysis, lipid metabolism, defense mechanisms, and amino acid storage-related functions. Subsequently, six target proteins were identified using labeled AzaA that interacted with whole insect proteins. In silico analysis suggests that AzaA could be efficiently accommodated in the hydrophobic pocket of juvenile hormone esterase and showed strong interaction with active site residues, indicating plausible targets of AzaA in H. armigera. Quantitative polymerase chain reaction analysis suggested differential gene expression patterns and partly corroborated the proteomic results. Overall, data suggest that AzaA generally targets more than one protein in H. armigera and hence could be a potent biopesticide.

Molecular engineering of an efficient four-domain DAF-MCP chimera reveals the presence of functional modularity in RCA proteins.

The complement system is highly efficient in targeting pathogens, but lack of its apposite regulation results in host-cell damage, which is linked to diseases. Thus, complement activation is tightly regulated by a series of proteins, which primarily belong to the regulators of complement activation (RCA) family. Structurally, these proteins are composed of repeating complement control protein (CCP) domains where two to four successive domains contribute to the regulatory functions termed decay-accelerating activity (DAA) and cofactor activity (CFA). However, the precise constitution of the functional units and whether these units can be joined to form a larger composition with dual function have not been demonstrated. Herein, we have parsed the functional units for DAA and CFA by constructing chimeras of the decay-accelerating factor (DAF) that exhibits DAA and membrane cofactor protein (MCP) that exhibits CFA. We show that in a four-CCP framework, a functional unit for each of the regulatory activities is formed by only two successive CCPs wherein each participates in the function, albeit CCP2 has a bipartite function. Additionally, optimal activity requires C-terminal domains that enhance the avidity of the molecule for C3b/C4b. Furthermore, by composing a four-CCP DAF-MCP chimera with robust CFA (for C3b and C4b) and DAA (for classical and alternative pathway C3 convertases), named decay cofactor protein, we show that CCP functional units can be linked to design a dual-activity regulator. These data indicate that the regulatory determinants for these two biological processes are distinct and modular in nature.

Dietary flavonoids inhibit the glycation of lens proteins: implications in the management of diabetic cataract.

The intervention of functional foods as complementary therapeutic approach for the amelioration of diabetes and sugar induced cataractogenesis is more appreciated over the present day chemotherapy agents owing to their nontoxic and increased bioavailability concerns. Dietary flavonoids, a class of bioactive phytochemicals is known to have wide range of biological activities against variety of human ailments. In the present study, we demonstrate anti-cataract effect of eight dietary flavonoids in sugar induced lens organ culture study. We present data on processes like inhibition of glycation-induced lens cloudiness, lens protein aggregation, glycation reaction and advanced glycation end products formation that can act as biochemical markers for this disease. The selected flavonoids were also tested for their aldose reductase (AR) inhibition (experimental and in silico). The molecular dynamics simulation results shed light on mechanistic details of flavonoid induced AR inhibition. The outcome of the present study clearly focuses the significance of kaempferol, taxifolin and quercetin as potential candidates for controlling diabetic cataract.

Characterization of structural and functional role of selenocysteine in selenoprotein H and its impact on DNA binding.

Selenoproteins are a group of proteins which contain selenocysteine (Sec or U) in their primary structure. Selenoproteins play a critical role in antioxidant defense, hormone metabolism, immune responses and muscle development. The selenoprotein H (SELENOH) is essential in the regulation of gene expression in response to redox status and antioxidant defense. It has Sec residue located in conserved CXXU motif similar to other selenoproteins. However, exact biological function of Sec residue in SELENOH is not known in detail. Therefore, it is essential to understand the structural and functional role of Sec in SELENOH. In the present study, homology modelling and MD simulation were performed to understand the role of Sec residue in SELENOH. The modelled 3D structure of wild-SELENOH along with two mutants (Mut-U44C and Mut-41CS-SC44) was subjected to MD simulation. Based on simulation results, we demonstrate that wild-SELENOH structure is dynamically stabilized by network of intramolecular hydrogen bonding and internal residue contacts facilitated by Sec residue. In contrast, notable differences have been observed in residue contacts and stability in other two mutant structures. Additionally, docking studies revealed that 3PRGRKRK9 motif of wild-SELENOH interacts with HSE and STRE of DNA molecule as observed experimentally. Similar to earlier reports, our sequence analysis study pinpoints conserved 3PRGRKRK9 motif present in SELENOH perform dual role as AT-hook motif and NLS. Overall, the obtained results clearly illustrate Sec residue plays an important role to restore functionally active conformation of SELENOH. The present study broadened our current understanding regarding the role of selenocysteine in protein structure and function.

Unravelling the structural interactions between PKR kinase domain and its small molecule inhibitors using computational approaches.

The RNA-dependent protein kinase (PKR), an eIF2α kinase plays an important role in anti-viral response, apoptosis and cell survival. It is also implicated to play a role in several cancers, metabolic and neurodegenerative disorders. A few ATP competitive inhibitors of the PKR have been reported in the literature with promising results in vitro and in vivo. The aim of this study was to unravel the structural interactions between these inhibitors and the PKR kinase domain using molecular simulations and docking. Our study reveals that the reported inhibitors bind in the adenine pocket and form hydrogen bonds with the hinge region and vdW interactions with non-polar residues in the binding site. The most potent inhibitor has several favorable interactions with the binding site and induces the P-loop to fold inward, creating a significant hydrophobic enclosure for itself. The computed binding free energies of these inhibitors are in accord with experimental data (IC50). Strategies to design potent and selective PKR inhibitors are discussed to overcome the reported promiscuity.

Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease.

Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. Various therapeutic approaches are being used to improve the cholinergic neurotransmission, but their role in AD pathogenesis is still unknown. Although, an increase in tau protein concentration in CSF has been described in AD, but several issues remains unclear. Extensive and accurate analysis of CSF could be helpful to define presence of tau proteins in physiological conditions, or released during the progression of neurodegenerative disease. The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aß) plaques in various areas of the brain. The amyloid hypothesis has continued to gain support over the last two decades, particularly from genetic studies. Therefore, current research progress in several areas of therapies shall provide an effective treatment to cure this devastating disease. This review critically evaluates general biochemical and physiological functions of Aß directed therapeutics and their relevance.

Structural analysis of membrane-bound hECE-1 dimer using molecular modeling techniques: insights into conformational changes and Aß1-42 peptide binding.

The human endothelin converting enzyme-1 (hECE-1) is a homodimer linked by a single disulfide bridge and has been identified as an important target for Alzheimer's disease. Structural analysis of hECE-1 dimer could lead to design specific and effective therapies against Alzheimer's disease. Hence, in the present study homology model of transmembrane helix has been constructed and patched with available crystal structure of hECE-1 monomer. Then, membrane-bound whole model of hECE-1 dimer has been developed by considering biophysical properties of membrane proteins. The explicit molecular dynamics simulation revealed that the hECE-1 dimer exhibits conformational restrains and controls total central cavity by regulating the degree of fluctuations in some residues (238-226) for substrate/product entrance/exit sites. In turn, conformational rearrangements of interdomain linkers as well as helices close to the inner surface are responsible for increasing total central cavity of hECE-1 dimer. Further, the model of hECE-1 dimer was docked with Aß1-42 followed by MD simulation to investigate possible orientation and interactions of Aß1-42 in catalytic groove of hECE-1 dimer. The free energy calculations exposed the stability of complex and helped us to identify key residues of hECE-1 involved in interactions with Aß1-42 peptide. Hence, the present study might be useful to understand structural significance of membrane-bound dimeric hECE-1 to design therapies against Alzheimer's disease.

Characterization of the algC gene expression pattern in the multidrug resistant Acinetobacter baumannii AIIMS 7 and correlation with biofilm development on abiotic surface.

Relative quantification of algC gene expression was evaluated in the multidrug resistant strain Acinetobacter baumannii AIIMS 7 biofilm (3 to 96 h, on polystyrene surface) compared to the planktonic counterparts. Comparison revealed differential algC expression pattern with maximum 81.59-fold increase in biofilm cells versus 3.24-fold in planktonic cells (P < 0.05). Expression levels strongly correlated with specific biofilm stages (scale of 3 to 96 h), coinciding maximum at initial surface attachment stage (9 h) and biofilm maturation stage (48 h). Cloning, heterologous expression, and bioinformatics analyses indicated algC gene product as the bifunctional enzyme phosphomannomutase/phosphoglucomutase (PMM/PGM) of ∼ 53 kDa size, which augmented biofilms significantly in algC clones compared to controls (lacking algC gene), further localized by scanning electron microscopy. Moreover, molecular dynamics analysis on the three-dimensional structure of PMM/PGM (simulated up to 10 ns) revealed enzyme structure as stable and similar to that in P. aeruginosa (synthesis of alginate and lipopolysaccharide core) and involved in constitution of biofilm EPS (extracellular polymeric substances). Our observation on differential expression pattern of algC having strong correlation with important biofilm stages, scanning electron-microscopic evidence of biofilm augmentation taken together with predictive enzyme functions via molecular dynamic (MD) simulation, proposes a new basis of A. baumannii AIIMS 7 biofilm development on inanimate surfaces.

Exploring mode of phosphoramidon and Aß peptide binding to hECE-1 by molecular dynamics and docking studies.

Human Endothelin converting enzyme (hECE-1) has been widely known for its involvement in hydrolyzing Aß peptides at multiple sites. In the present study we have performed molecular dynamics (MD) simulation of crystal structure complex of hECE-1 and its inhibitor phosphoramidon with Zn ion to understand the dynamic behavior of active site residues. Root Mean Square Deviation (RMSD) results revealed that enzyme hECE-1 structure was highly stable throughout the simulation period. The L-leucyl-L-tryptophan moiety and N-phosphoryl moiety of phosphoramidon was found in the S1 and S2 pockets of hECE-1 respectively. The inhibitor was stabilized by hydrogen bonding interactions with residues Arg 145, Asn 566, Pro 731 and His 732 of hECE-1. Based on this information molecular docking of hECE- 1 crystal structure with three different structures of Aß peptides has been performed. Zinc ion interacts with His 607(NE2), His 611(NE2), Glu 667 (OE1, OE2) and backbone oxygen atom of Phe 19 showing catalytic coordination between Aß peptide and hECE-1. The unusual orientation of Aß peptide residues affects hydrophobic interactions and hydrogen bonding network between hECE-1 and Aß peptide. The molecular basis of amyloid beta peptide cleavage by hECE-1 could aid in designing enzyme based therapies to control Aß peptide concentration in Alzheimer's patient.

Homology modeling, molecular docking and MD simulation studies to investigate role of cysteine protease from Xanthomonas campestris in degradation of Aß peptide.

Cysteine protease is known to degrade amyloid beta peptide which is a causative agent of Alzheimer's disease. This cleavage mechanism has not been studied in detail at the atomic level. Hence, a three-dimensional structure of cysteine protease from Xanthomonas campestris was constructed by homology modeling using Geno3D, SWISS-MODEL, and MODELLER 9v7. All the predicted models were analyzed by PROCHECK and PROSA. Three-dimensional model of cysteine protease built by MODELLER 9v7 shows similarity with human cathepsin B crystal structure. This model was then used further for docking and simulation studies. The molecular docking study revealed that Cys17, His87, and Gln88 residues of cysteine protease form an active site pocket similar to human cathepsin B. Then the docked complex was refined by molecular dynamic simulation to confirm its stable behavior over the entire simulation period. The molecular docking and MD simulation studies showed that the sulfhydryl hydrogen atom of Cys17 of cysteine protease interacts with carboxylic oxygen of Lys16 of Aß peptide indicating the cleavage site. Thus, the cysteine protease model from X. campestris having similarity with human cathepsin B crystal structure may be used as an alternate approach to cleave Aß peptide a causative agent of Alzheimer's disease.

Homology modeling, molecular docking and DNA binding studies of nucleotide excision repair UvrC protein from M. tuberculosis.

Mycobacterium tuberculosis is a Gram positive, acid-fast bacteria belonging to genus Mycobacterium, is the leading causative agent of most cases of tuberculosis. The pathogenicity of the bacteria is enhanced by its developed DNA repair mechanism which consists of machineries such as nucleotide excision repair. Nucleotide excision repair consists of excinuclease protein UvrABC endonuclease, multi-enzymatic complex which carries out repair of damaged DNA in sequential manner. UvrC protein is a part of this complex and thus helps to repair the damaged DNA of M. tuberculosis. Hence, structural bioinformatics study of UvrC protein from M. tuberculosis was carried out using homology modeling and molecular docking techniques. Assessment of the reliability of the homology model was carried out by predicting its secondary structure along with its model validation. The predicted structure was docked with the ATP and the interacting amino acid residues of UvrC protein with the ATP were found to be TRP539, PHE89, GLU536, ILE402 and ARG575. The binding of UvrC protein with the DNA showed two different domains. The residues from domain I of the protein VAL526, THR524 and LEU521 interact with the DNA whereas, amino acids interacting from the domain II of the UvrC protein included ARG597, GLU595, GLY594 and GLY592 residues. This predicted model could be useful to design new inhibitors of UvrC enzyme to prevent pathogenesis of Mycobacterium and so the tuberculosis.

Molecular dynamics simulation and molecular docking studies of Angiotensin converting enzyme with inhibitor lisinopril and amyloid Beta Peptide.

Angiotensin converting enzyme (ACE) cleaves amyloid beta peptide. So far this cleavage mechanism has not been studied in detail at atomic level. Keeping this view in mind, we performed molecular dynamics simulation of crystal structure complex of testis truncated version of ACE (tACE) and its inhibitor lisinopril along with Zn(2+) to understand the dynamic behavior of active site residues of tACE. Root mean square deviation results revealed the stability of tACE throughout simulation. The residues Ala 354, Glu 376, Asp 377, Glu 384, His 513, Tyr 520 and Tyr 523 of tACE stabilized lisinopril by hydrogen bonding interactions. Using this information in subsequent part of study, molecular docking of tACE crystal structure with Aß-peptide has been made to investigate the interactions of Aß-peptide with enzyme tACE. The residues Asp 7 and Ser 8 of Aß-peptide were found in close contact with Glu 384 of tACE along with Zn(2+). This study has demonstrated that the residue Glu 384 of tACE might play key role in the degradation of Aß-peptide by cleaving peptide bond between Asp 7 and Ser 8 residues. Molecular basis generated by this attempt could provide valuable information towards designing of new therapies to control Aß concentration in Alzheimer's patient.