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Biomedical subjects

G Narahari Sastry

Publications and source records attributed to G Narahari Sastry.

At least 19 recordsLinked to original sources
PubMed2007

Towards design of the smallest planar tetracoordinate carbon and boron systems.

A series of cyclic hydrocarbons analogs where a carbon displays unusual planar tetracoordinate structure is proposed, employing hybrid density functional theory calculations using B3LYP functional and 6-311+G** basis set. Various strategies were employed to design the neutral planar tetracoordinate hydrocarbon analogs. The same strategy is employed for designing the planar tetracoordinate boron systems. The simplest neutral planar tetracoordinate hydrocarbons were proposed and the effect of substitution on their stability has been assessed. The aromatic stabilization is gauged with nucleus independent chemical shift calculations. The activation barriers for the ring opening reaction, the highest occupied molecular orbital and lowest unoccupied molecular orbitals gap and singlet-triplet energy difference were estimated to gauge the plausibility experimental realization.

Boron↗
PubMed2007

Strategies to design pyrazolyl urea derivatives for p38 kinase inhibition: a molecular modeling study.

The p38 protein kinase is a serine-threonine mitogen activated protein kinase, which plays an important role in inflammation and arthritis. A combined study of 3D-QSAR and molecular docking has been undertaken to explore the structural insights of pyrazolyl urea p38 kinase inhibitors. The 3D-QSAR studies involved comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The best CoMFA model was derived from the atom fit alignment with a cross-validated r (2 )(q (2)) value of 0.516 and conventional r (2) of 0.950, while the best CoMSIA model yielded a q (2) of 0.455 and r (2) of 0.979 (39 molecules in training set, 9 molecules in test set). The CoMFA and CoMSIA contour maps generated from these models provided inklings about the influence of interactive molecular fields in the space on the activity. GOLD, Sybyl (FlexX) and AutoDock docking protocols were exercised to explore the protein-inhibitor interactions. The integration of 3D-QSAR and molecular docking has proffered essential structural features of pyrazolyl urea inhibitors and also strategies to design new potent analogues with enhanced activity.

Drug Design↗
PubMed2006

A computational study on pi and sigma modes of metal ion binding to heteroaromatics (CH)(5-m)X(m) and (CH)(6-m)X(m) (X = N and P): contrasting preferences between nitrogen- and phosphorous-substituted rings.

The pi and sigma complexation energy of various heteroaromatic systems which include mono-, di-, and trisubstituted azoles, phospholes, azines and phosphinines with various metal ions, viz. Li(+), Na(+), K(+), Mg(2+), and Ca(2+), was calculated at the post Hartree-Fock MP2 level, MP2(FULL)/6-311+G(2d,2p)//MP2/6-31G. The azoles and azines were found to form stronger sigma complexes than the corresponding pi complexes, whereas the phospholes and phosphinines had higher pi complexation energy with Li(+), Mg(2+), and Ca(2+) while their pi and sigma complexation energies were very comparable with Na(+) and K(+). The strongest pi complex among the five-membered heteroaromatic system was that of pyrrole with all the metals except with Mg(2+), while benzene formed the strongest pi complex among the six-membered heterocyclic systems. The nitrogen heterocyclic system 4H-[1,2,4] triazole and pyridazine formed the strongest sigma complex among the five- and six-membered heteroaromatic systems considered. The complexation energy of the pi and sigma complexes of the azoles and azines was found to decrease with the increase in the heteroatom substitution in the ring, while that of phospholes and phosphinines did not vary significantly. The azoles and azines preferred to form sigma complexes wherein the metal had bidentate linkage, while the phospholes and phosphinines did not show binding mode preference. In the sigma complexes of both azoles and phospholes, the metal binds away form the electron-deficient nitrogen or phosphorus center.

Computer Simulation↗
PubMed2006

Formation of linear polymers with pendant vinyl groups via inclusion complex mediated polymerization of divinyl monomers.

Ethylene glycol dimethacrylate (EGDMA) and ethylene glycol methacrylate 4-vinyl benzoate (EGMAVB) were shown to form 1:1 inclusion complexes with cyclodextrin and were characterized by instrumental techniques. Computational analysis showed that the bent conformation of the included divinyl monomer was more stable than its linear conformation. Complexation of the divinyl monomer with the first CD molecule offered substantial stabilization than with the second CD molecule. The vinyl group included in the CD cavity did not participate in polymerization. As a result, solvent soluble, linear polymers with pendant vinyl unsaturation per repeat unit were obtained. This was unequivocally established by the polymerization of a complex comprising CD and EGMAVB. The unreacted vinyl group can be polymerized in the subsequent step to yield cross-linked products.

Biocompatible Materials↗
PubMed2006

Active site acidic residues and structural analysis of modelled human aromatase: a potential drug target for breast cancer.

This study sheds new light on the role of acidic residues present in the active site cavity of human aromatase. Eight acidic residues (E129, D222, E245, E302, D309, E379, D380 and D476) lining the cavity are identified and studied using comparative modeling, docking, molecular dynamics as well as statistical techniques. The structural environment of these acidic residues is studied to assess the stability of the corresponding carboxylate anions. Results indicate that the environment of the residues E245, E302 and D222 is most suitable for carboxylate ion formation in the uncomplexed form. However, the stability of D309, D222 and D476 anions is seen to increase on complexation to steroidal substrates. In particular, the interaction between D309 and T310, which assists proton transfer, is found to be formed following androgen/nor-androgen complexation. The residue D309 is found to be clamped in the presence of substrate which is not observed in the case of the other residues although they exhibit changes in properties following substrate binding. Information entropic analysis indicates that the residues D309, D222 and D476 have more conformational flexibility compared to E302 and E245 prior to substrate binding. Interaction similar to that between D476 and D309, which is expected to assist androgen aromatization, is proposed between E302 and E245. The inhibition of aromatase activity by 4-hydroxy androstenedione (formestane) is attributed to a critical hydrogen bond formation between the hydroxy moiety and T310/D309 as well as the large distance from D476. The results corroborate well with earlier site directed mutagenesis studies.

Amino Acids, Acidic↗
PubMed2006

Homology modeling of membrane proteins: a critical assessment.

Evaluation and validation of homology modeling protocols are indispensable for membrane proteins as experimental determination of their three-dimensional structure is an arduous task. The prediction ability of Modeller, MOE, InsightII-Homology and Swiss-PdbViewer (SPV) with different sequence alignments CLUSTALW, BLAST and 3D-JIGSAW have been assessed. The sequence identity of the target and template was chosen to be in the range of 25-35%. Validation protocols to assess the structure, fold and stereochemical quality, are employed by comparing with experimental structures. Two different ranking schemes are suggested to evaluate the performance of each methodology based on the validation scores. While unambiguous preference for any given procedure did not surface, statistically Modeller and the sequence alignment technique, 3D-JIGSAW, gave best results amongst the chosen protocols. The present study helps in selecting the right protocols when modeling membrane proteins, which form a major class of drug targets.

Computational Biology↗
PubMed2006

From subtle to substantial: role of metal ions on pi-pi interactions.

Quantum chemistry calculations reveal that the subtle pi-pi interactions, usually in the range 2-4 kcal/mol, will become substantially significant, from 6 to 17 kcal/mol, in the presence of metal ion. The metal ions have higher affinity toward a pi-pi dimer compared to a single pi-moiety. Considering the widespread occurrence of cation-pi-pi motifs in chemistry and biology, as evident from the database analysis, we propose that the two key noncovalent forces, which govern the macromolecular structure, cation-pi and pi-pi, work in concert.

Cations↗
PubMed2006

DSTHO: database of siRNAs targeted at human oncogenes: a statistical analysis.

Existing treatments of human cancer, which is characterized by abnormal proliferation of cells often lead to fatal outcomes. Sequence selective silencing of oncogene expression using siRNA technology is emerging as a potential solution for cancer treatment. The exclusive selectivity and easy application to virtually any therapeutic target including intracellular factors and transcription factors renders siRNA oligonucleotide applications very promising. However, synthesis of siRNA having sufficient knockdown efficiency is laborious and cost intensive. The database is designed in order to aid the synthesis of siRNAs, which target human oncogenes (OsiRNAs). It provides OsiRNAs of known efficacy from previous experiments with links to published literature and theoretically pre-generated putative target sequences. In addition, links to available theoretical tools, databases and literature corresponding to siRNAs in general are also provided. The links to literature provide information about role of siRNA in therapeutics, chemical properties and transfection methods. Statistical analysis of mono-, di- and tri- mers located in OsiRNAs of known efficacies is performed to identify positional preferences and screen specific motifs. This analysis aids the design and synthesis of effective siRNAs, which particularly target human oncogenes. The database can be accessed at .

Base Composition↗
PubMed2006

Generation of regiospecific carbanions under electrospray ionisation conditions and their selectivity in ion-molecule reactions with CO2.

Regiospecific formation of carbanions from a set of geometrical (cis and trans isomers) and five different sets of positional isomers (ortho, meta and para isomers) of aromatic carboxylic acids is reported under negative electrospray ionisation conditions by decarboxylation of the carboxylate anions. The structures of decarboxylated anions, [(M-H)-CO(2)](-), are studied by ion-molecule reactions with carbon dioxide in the collision cell of a triple quadrupole mass spectrometer. The [(M-H)-CO(2)](-) ions generated from the trans and meta/para isomers react with CO(2) to produce product ions corresponding to the addition of one CO(2), which confirms the survival of the [(M-H)-CO(2)](-) ions as carbanions. On the other hand, the [(M-H)-CO(2)](-) ions generated from cis and ortho isomers failed to react with CO(2) due to rapid isomerisation of the initially generated carbanion to a aromatic carboxylate/oxide anion, which is unreactive with CO(2), through a facile intramolecular proton transfer from the proton-containing substituent to the carbanion site. When the experiments were performed at high desolvation temperatures (300 degrees C), instead of 100 degrees C, the relative abundance of [(M-H)-CO(2)](-) ions and the corresponding CO(2) adduct in ion-molecule reaction experiments increased significantly due to minimisation of proton exchange. Quantum chemical calculations on some of the generated isomeric carbanions and their isomerised products due to proton transfer support the selective stability of carbanions.

Journal Article↗
PubMed2006

Choline kinase: an important target for cancer.

Choline kinase (ChoK) is a cytosolic enzyme present in various tissues, which catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is important for the generation of two major membrane phospholipids, phosphatidylcholine (PC) and sphingomyelin (SM) and subsequently for the cell division. ChoK plays a vital role in cell signaling pathways and regulation of cell growth along with PCho involved in malignant transformation through ras oncogenes in different cancers such as breast, lung, colon, prostate, neuroblastoma, hepatic lymphomas, meningiomas and diverse murine tumours. The Ras effectors serine/threonine kinase (Raf-1), the Ral-GDP dissociation stimulator (Ral-GDS) and the phosphatidylinositol 3-kinase (PI3K) are involved in the activation of ChoK during tumorigenesis. ChoK gene induction seems to be associated with certain cell stress or cell defense. Nowadays, RNAi appear to be one of the most promising routes in the cancer therapy. The anticancer potential of both stable expression of siRNAs and their high sequence specificity by RNAi mediated suppression of oncogenic ras in human pancreatic carcinoma, human melanomas and ovarian cancer has been observed. It has an important role in sequence specific post-transcriptional gene silencing mechanism. Presently, the crystal structure of Caenorhabditis elegans choline kinase A-2 (ChoKA-2) is available, which may be useful for comparative modeling of human ChoK and further modeling studies. The present review aims at the general overview of importance, expression, structure, progress in molecular modeling, active site analysis and inhibitors of ChoK. It also highlights the recent role of ChoK in various types of Ras-dependent and Ras-independent carcinogenesis.

Animals↗
PubMed2006

Novel targets for antiinflammatory and antiarthritic agents.

Inflammation is a complex pathological condition associated with exaggerated human immune system involving various activated immune cells and bio-molecules. Treatment of inflammatory diseases particularly chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease etc. has been a big challenge for scientists as there are no safe drugs available for cure. Current therapeutic approaches to the treatment of inflammatory diseases are centered on cycloxygenase (both COX-1 and 2) proinflammatory enzymes but present available drugs of this category are associated with undesirable gastrointestinal and cardiovascular side effects. Recent scientific advents draw out the secrets of inflammation cache and understanding the involvement of several factors acting as stimulators or inhibitors thus opening new avenues for drug discoveries. Several bio-molecules such as proinflammatory cytokines, components of signal transduction and matrix degrading enzymes resolve inflammatory responses, might be new targets for treatment of chronic inflammatory diseases. This review gathers recent advances in drug research focusing interleukin-1, TNF-alpha, p38 kinase, c-Jun N-terminal kinase MAP kinase, NFkappaB, and matrix metalloproteinases. The biological roles of these inflammatory mediators are clearly understood thus offering new targets for design of novel inhibitors for incurable inflammatory diseases. This also provides an overview of the current nonsteroidal antiinflammatory agents.

Anti-Inflammatory Agents↗
PubMed2006

Recent advances in molecular modeling and medicinal chemistry aspects of phospho-glycoprotein.

Phospho-glycoprotein (P-gp) is an efflux transporter expressed in many organs (ex: kidney, lung, liver and spleen) and in hormone producing or responsive tissues (ex: adrenal cortex, testis and placenta). It is involved in many important physiological functions. Among them the major one is extrusion of xenobiotics in order to detoxify the cells. This property of P-gp is associated with multidrug resistance (MDR) for many pathological conditions. While the experimental determination of three-dimensional structure is not yet successful, the transmembrane (TM) 5, 6, 11 and 12 are sensitive to mutations and contain substrate binding sites. Designing of potential and selective inhibitors of P-gp is still hampered by a lack of information upon the three dimensional structure of P-gp. The design of P-gp inhibitors was traditionally driven by quantitative structure activity relationship studies, which is complicated by factors such as different types of assays, multiple drug binding sites and diverse chemical structures. Clearly a conclusive and predictive SAR does not seem to be practical, despite progress in the last few years towards more specific SAR suggesting well defined structural features responsible for activity. Advances made recently in solving the crystal structure of prokaryotic ATP binding cassette proteins (ABC) transporters, Ec-MsbA, Vc-MsbA and BtuCD yielded suitable templates for construction of homology models of P-gp. Few molecular dynamics (MD) simulations aimed at elucidating the functional dynamics of ABC transporters have provided useful insights to their mechanism and structure. The present review aims at the general overview of importance, expression, structure, organization and drug binding sites of P-gp. This review also highlights recent developments in the homology modeling, molecular dynamics simulations of P-gp and progress in QSAR, pharmacophore modeling of P-gp modulators.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Proton binding sites and conformational analysis of H+K(+)-ATPase.

It is proposed that the hydronium ion, H3O+, binds to the E1 conformation of the alpha-subunit of gastric proton pump. The H3O+ binding cavities are characterized parametrically based on valence, sequence, geometry, and size considerations from comparative modeling. The cavities have scope for accommodating monovalent cations of different ionic radii. The H3O+ transport is proposed to be aided by arenes which are arranged regularly along the pump starting from N-domain through the transmembrane region. Step-by-step structural changes accompanying H3O+ occlusion are studied in detail. The observations corroborate well with earlier experimental studies.

Adenosine Triphosphate↗
PubMed2005

Competitive Diels-Alder reactions: cyclopentadiene and phospholes with butadiene.

Diene-dienophile competing Diels-Alder reaction pathways of cyclopentadiene, 1H-, 2H- and 3H-phospholes with butadiene were explored at the B3LYP level using 6-31G(d) and 6-311+G(d,p) basis sets, and at the CCSD(T)/6-31G(d)//B3LYP/6-31G(d) level. Activation barriers show that cyclopentadiene favors a diene rather than a dienophile conformation. Pathways 1 and 2 (A and B) corresponding to butadiene as the diene and dienophile are predicted to be highly competitive in the case of 1H-phosphole. Secondary orbital interactions and the preferable bispericyclic nature of transition states are responsible for the stability of endo transition states. The study indicates that some of the transition states are bispericyclic and most of them are highly asynchronous. The reactions require a lower activation energy when the conversion of weak C=P to C-P occurs in the case of 2H- and 3H-phospholes. The high stability of the products resulting via path 1 can be attributed to the less strain in the bicyclo[4.3.0]nonadiene skeleton compared to the norbornene derivatives obtained from path 2. Activation and reaction energy values for these Diels-Alder reaction pathways are compared with the values reported for the [4+2] cyclodimerizations of each of the reactants to examine the likelihood of cyclodimerizations along these pathways.

Journal Article↗
PubMed2005

Structural and active site analysis of plasmepsins of Plasmodium falciparum: potential anti-malarial targets.

Comparative protein modeling, active site analysis and binding site specificity for the homologous series of plasmepsins (PM's), present in food vacuole of Plasmodium falciparum, are carried out. Four loops (L1, L2, L3 and L4), which show maximum structural deviations irrespective of type of inhibitor, have been identified. Comparison of the crystal structures of ligand complexes reveal that residues belonging to these loops have negligible coulomb and VDW interactions with the inhibitor but play major role in determining the openness of the binding cavity. The coulomb and VDW interactions between the PMII subsite pockets and inhibitors, which play a major role in determining the inhibition constants, are delineated. Besides small displacements, the catalytic residues D32 of PMII undergoes rotation around the Cgamma-Cbeta single bond to assist catalysis whereas side chain conformational deviations are not observed in D214 on plasmepsin activation. The mutant S79D of PMII (and the corresponding residues of PMI and PMIV) which helps in recognizing and cleaving substrates containing lysine at P1 position is surrounded by highly polar atmosphere stabilized by lysine. However, in PMIII significantly lower polar atmosphere around the mutant A78S/A78D is observed. Large buried side chain area of residues located at M15 and I289 of PMII (and corresponding residues of PMI and PMIV) corroborates well with increase in specificity constant for hydrophobic substrates.

Amino Acid Sequence↗
PubMed2005

Cation [M = H+, Li+, Na+, K+, Ca2+, Mg2+, NH4+, and NMe4+] interactions with the aromatic motifs of naturally occurring amino acids: a theoretical study.

Ab initio (HF, MP2, and CCSD(T)) and DFT (B3LYP) calculations were done in modeling the cation (H(+), Li(+), Na(+), K(+), Ca(2+), Mg(2+), NH(4)(+), and NMe(4)(+)) interaction with aromatic side chain motifs of four amino acids (viz., phenylalanine, tyrosine, tryptophan and histidine). As the metal ion approaches the pi-framework of the model systems, they form strongly bound cation-pi complexes, where the metal ion is symmetrically disposed with respect to all ring atoms. In contrast, proton prefers to bind covalently to one of the ring carbons. The NH(4)(+) and NMe(4)(+) ions have shown N-H...pi interaction and C-H...pi interaction with the aromatic motifs. The interaction energies of N-H...pi and C-H...pi complexes are higher than hydrogen bonding interactions; thus, the orientation of aromatic side chains in protein is effected in the presence of ammonium ions. However, the regioselectivity of metal ion complexation is controlled by the affinity of the site of attack. In the imidazole unit of histidine the ring nitrogen has much higher metal ion (as well as proton) affinity as compared to the pi-face, facilitating the in-plane complexation of the metal ions. The interaction energies increase in the order of 1-M < 2-M < 3-M < 4-M < 5-M for all the metal ion considered. Similarly, the complexation energies with the model systems decrease in the following order: Mg(2+) > Ca(2+) > Li(+) > Na(+) > K(+) congruent with NH(4)(+) > NMe(4)(+). The variation of the bond lengths and the extent of charge transfer upon complexation correlate well with the computed interaction energies.

Amino Acid Motifs↗