25 results on '"Mulpuri, Nagaraju"'
Search Results
2. Reaction Path-Force Matching in Collective Variables: Determining Ab Initio QM/MM Free Energy Profiles by Fitting Mean Force
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Ryan Snyder, Bryant Kim, Yihan Shao, Pedro Ojeda-May, Mellisa M. Hege, Seth Keeton, Jingzhi Pu, Mulpuri Nagaraju, and Yan Zhou
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Physics ,Range (particle radiation) ,Mathematical analysis ,Ab initio ,Potential energy ,Article ,Computer Science Applications ,QM/MM ,Spline (mathematics) ,symbols.namesake ,symbols ,Density functional theory ,Physical and Theoretical Chemistry ,Hamiltonian (quantum mechanics) ,Energy (signal processing) - Abstract
First-principles determination of free energy profiles for condensed-phase chemical reactions is hampered by the daunting costs associated with configurational sampling on ab initio quantum mechanical/molecular mechanical (AI/MM) potential energy surfaces. Here, we report a new method that enables efficient AI/MM free energy simulations through mean force fitting. In this method, a free energy path in collective variables (CVs) is first determined on an efficient reactive aiding potential. Based on the configurations sampled along the free energy path, correcting forces to reproduce the AI/MM forces on the CVs are determined through force matching. The AI/MM free energy profile is then predicted from simulations on the aiding potential in conjunction with the correcting forces. Such cycles of correction-prediction are repeated until convergence is established. As the instantaneous forces on the CVs sampled in equilibrium ensembles along the free energy path are fitted, this procedure faithfully restores the target free energy profile by reproducing the free energy mean forces. Due to its close connection with the reaction path-force matching (RP-FM) framework recently introduced by us, we designate the new method as RP-FM in collective variables (RP-FM-CV). We demonstrate the effectiveness of this method on a type-II solution-phase S(N)2 reaction, NH(3) + CH(3)Cl (the Menshutkin reaction), simulated with an explicit water solvent. To obtain the AI/MM free energy profiles, we employed the semiempirical AM1/MM Hamiltonian as the base level for determining the string minimum free energy pathway, along which the free energy mean forces are fitted to various target AI/MM levels using the Hartree-Fock (HF) theory, density functional theory (DFT), and the second-order MØller-Plesset perturbation (MP2) theory as the AI method. The forces on the bond-breaking and bond-forming CVs at both the base and target levels are obtained by force transformation from Cartesian to redundant internal coordinates under the Wilson B-matrix formalism, where the linearized FM is facilitated by the use of spline functions. For the Menshutkin reaction tested, our FM treatment greatly reduces the deviations on the CV forces, originally in the range of 12~33 to ∼2 kcal/mol/Å. Comparisons with the experimental and benchmark AI/MM results, tests of the new method under a variety of simulation protocols, and analyses of the solute-solvent radial distribution functions suggest that RP-FM-CV can be used as an efficient, accurate, and robust method for simulating solution-phase chemical reactions.
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- 2021
3. A scoring function for the prediction of protein complex interfaces based on the neighborhood preferences of amino acids
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Mulpuri Nagaraju and Haiguang Liu
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Molecular Docking Simulation ,Structural Biology ,Protein Conformation ,Proteins ,Thermodynamics ,Amino Acids ,Protein Binding - Abstract
Proteins often assemble into functional complexes, the structures of which are more difficult to obtain than those of the individual protein molecules. Given the structures of the subunits, it is possible to predict plausible complex models via computational methods such as molecular docking. Assessing the quality of the predicted models is crucial to obtain correct complex structures. Here, an energy-scoring function was developed based on the interfacial residues of structures in the Protein Data Bank. The statistically derived energy function (Nepre) imitates the neighborhood preferences of amino acids, including the types and relative positions of neighboring residues. Based on the preference statistics, a program iNepre was implemented and its performance was evaluated with several benchmarking decoy data sets. The results show that iNepre scores are powerful in model ranking to select the best protein complex structures.
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- 2022
4. Mapping Free Energy Pathways for ATP Hydrolysis in the E. coli ABC Transporter HlyB by the String Method
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Yan Zhou, Pedro Ojeda-May, Mulpuri Nagaraju, Bryant Kim, and Jingzhi Pu
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QM/MM ,free energy simulations ,ABC transporter ,ATP hydrolysis ,string method ,minimum free energy path ,proton transfer ,Organic chemistry ,QD241-441 - Abstract
HlyB functions as an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that enables bacteria to secrete toxins at the expense of ATP hydrolysis. Our previous work, based on potential energy profiles from combined quantum mechanical and molecular mechanical (QM/MM) calculations, has suggested that the highly conserved H-loop His residue H662 in the nucleotide binding domain (NBD) of E. coli HlyB may catalyze the hydrolysis of ATP through proton relay. To further test this hypothesis when entropic contributions are taken into account, we obtained QM/MM minimum free energy paths (MFEPs) for the HlyB reaction, making use of the string method in collective variables. The free energy profiles along the MFEPs confirm the direct participation of H662 in catalysis. The MFEP simulations of HlyB also reveal an intimate coupling between the chemical steps and a local protein conformational change involving the signature-loop residue S607, which may serve a catalytic role similar to an Arg-finger motif in many ATPases and GTPases in stabilizing the phosphoryl-transfer transition state.
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- 2018
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5. Cyclophilin A Inhibition: Targeting Transition-State-Bound Enzyme Conformations for Structure-Based Drug Design.
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Mulpuri Nagaraju, Lauren C. McGowan, and Donald Hamelberg
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- 2013
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6. Elucidating the role of surface passivating ligand structural parameters in hole wave function delocalization in semiconductor cluster molecules
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Meghan B. Teunis, Poulami Dutta, Mangilal Agarwal, Rajesh Sardar, Barry B. Muhoberac, Jingzhi Pu, and Mulpuri Nagaraju
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Materials science ,Photoluminescence ,business.industry ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,Delocalized electron ,chemistry.chemical_compound ,Semiconductor ,chemistry ,Computational chemistry ,Absorption band ,Monolayer ,Physical chemistry ,Molecule ,General Materials Science ,Density functional theory ,Carboxylate ,0210 nano-technology ,business - Abstract
This article describes the mechanisms underlying electronic interactions between surface passivating ligands and (CdSe)34 semiconductor cluster molecules (SCMs) that facilitate band-gap engineering through the delocalization of hole wave functions without altering their inorganic core. We show here both experimentally and through density functional theory calculations that the expansion of the hole wave function beyond the SCM boundary into the ligand monolayer depends not only on the pre-binding energetic alignment of interfacial orbitals between the SCM and surface passivating ligands but is also strongly influenced by definable ligand structural parameters such as the extent of their π-conjugation [π-delocalization energy; pyrene (Py), anthracene (Anth), naphthalene (Naph), and phenyl (Ph)], binding mode [dithiocarbamate (DTC, –NH–CS2−), carboxylate (–COO−), and amine (–NH2)], and binding head group [–SH, –SeH, and –TeH]. We observe an unprecedentedly large ∼650 meV red-shift in the lowest energy optical absorption band of (CdSe)34 SCMs upon passivating their surface with Py-DTC ligands and the trend is found to be Ph- < Naph- < Anth- < Py-DTC. This shift is reversible upon removal of Py-DTC by triethylphosphine gold(I) chloride treatment at room temperature. Furthermore, we performed temperature-dependent (80–300 K) photoluminescence lifetime measurements, which show longer lifetime at lower temperature, suggesting a strong influence of hole wave function delocalization rather than carrier trapping and/or phonon-mediated relaxation. Taken together, knowledge of how ligands electronically interact with the SCM surface is crucial to semiconductor nanomaterial research in general because it allows the tuning of electronic properties of nanomaterials for better charge separation and enhanced charge transfer, which in turn will increase optoelectronic device and photocatalytic efficiencies.
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- 2017
7. Dual Role of Electron-Accepting Metal-Carboxylate Ligands: Reversible Expansion of Exciton Delocalization and Passivation of Nonradiative Trap-States in Molecule-like CdSe Nanocrystals
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Barry B. Muhoberac, Meghan B. Teunis, Rajesh Sardar, Katie N. Lawrence, Poulami Dutta, and Mulpuri Nagaraju
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Exciton ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Photochemistry ,01 natural sciences ,Biochemistry ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Delocalized electron ,Colloid and Surface Chemistry ,chemistry ,Oleylamine ,Bathochromic shift ,Molecule ,Carboxylate ,0210 nano-technology ,HOMO/LUMO ,Powder diffraction - Abstract
This paper reports large bathochromic shifts of up to 260 meV in both the excitonic absorption and emission peaks of oleylamine (OLA)-passivated molecule-like (CdSe)34 nanocrystals caused by postsynthetic treatment with the electron accepting Cd(O2CPh)2 complex at room temperature. These shifts are found to be reversible upon removal of Cd(O2CPh)2 by N,N,N′,N′-tetramethylethylene-1,2-diamine. 1H NMR and FTIR characterizations of the nanocrystals demonstrate that the OLA remained attached to the surface of the nanocrystals during the reversible removal of Cd(O2CPh)2. On the basis of surface ligand characterization, X-ray powder diffraction measurements, and additional control experiments, we propose that these peak red shifts are a consequence of the delocalization of confined exciton wave functions into the interfacial electronic states that are formed from interaction of the LUMO of the nanocrystals and the LUMO of Cd(O2CPh)2, as opposed to originating from a change in size or reorganization of the inorg...
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- 2016
8. Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents
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Michelle D. Reid, Mulpuri Nagaraju, Manu Lopus, Donald Hamelberg, Vibha Tandon, Prasanthi Karna, Sushma R. Gundala, Ritu Aneja, Kamlesh K. Gupta, Ram Chandra Mishra, and Dulal Panda
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Anticancer Activity ,Tubulin Polymerization ,Models, Molecular ,Noscapine ,Lymphoma ,Cell division ,Perturb Mitosis ,Cells ,Survivin ,Resistance ,Clinical Biochemistry ,Pharmaceutical Science ,Apoptosis ,Antineoplastic Agents ,Pharmacology ,Microtubules ,Biochemistry ,Article ,Tubulin binding ,Cancer Therapeutics ,Microtubule ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Molecular Biology ,Tumors ,biology ,Chemistry ,Tubulin Isotypes ,Organic Chemistry ,Biological activity ,Cell cycle ,Tubulin ,Drug Design ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
Noscapine is an opium-derived kinder-gentler microtubule-modulating drug, currently in Phase I/II clinical trials for cancer chemotherapy. Here, we report the synthesis of four more potent di-substituted brominated derivatives of noscapine, 9-Br-7-OH-NOS (2), 9-Br-7-OCONHEt-NOS (3), 9-Br-7-OCONHBn-NOS (4), and 9-Br-7-OAc-NOS (5) and their chemotherapeutic efficacy on PC-3 and MDA-MB-231 cells. The four derivatives were observed to have higher tubulin binding activity than noscapine and significantly affect tubulin polymerization. The equilibrium dissociation constant (K-D) for the interaction between tubulin and 2, 3, 4, 5 was found to be, 55 +/- 6 mu M, 44 +/- 6 mu M, 26 +/- 3 mu M, and 21 +/- 1 mu M respectively, which is comparable to parent analog. The effects of these di-substituted noscapine analogs on cell cycle parameters indicate that the cells enter a quiescent phase without undergoing further cell division. The varying biological activity of these analogs and bulk of substituent at position-7 of the benzofuranone ring system of the parent molecule was rationalized utilizing predictive in silico molecular modeling. Furthermore, the immunoblot analysis of protein lysates from cells treated with 4 and 5, revealed the induction of apoptosis and down-regulation of survivin levels. This result was further supported by the enhanced activity of caspase-3/7 enzymes in treated samples compared to the controls. Hence, these compounds showed a great potential for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers. (C) 2015 Elsevier Ltd. All rights reserved.
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- 2015
9. Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity
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Sushma R. Gundala, Yogesh Yadav, Donald Hamelberg, Lakshminarayana Narayana, Shazia Ahad, Rao Mukkavilli, Vibha Tandon, Ritu Aneja, Vibhuti Sharma, Maged Henary, Mulpuri Nagaraju, Dulal Panda, and Eric A. Owens
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Male ,Noscapine ,Perturb Mitosis ,Cells ,Pharmacology ,Microtubules ,Biochemistry ,Protein Structure, Secondary ,Article ,Tubulin binding ,Mice ,In vivo ,Complex ,medicine ,Animals ,Humans ,Pharmacokinetics ,Solubility ,Cancer ,Cell Proliferation ,Dose-Response Relationship, Drug ,biology ,Chemistry ,Tubulin Modulators ,Goats ,Water ,Tubulin Binding ,Molecules ,Growth Inhibitors ,Dynamics ,Bioavailability ,Tubulin ,Docking (molecular) ,Water Solubility ,biology.protein ,Biophysics ,Antiproliferative ,Force-Field ,HeLa Cells ,medicine.drug - Abstract
Noscapine, an opium-derived 'kinder-gentler' microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a-c; 8a-c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and Sc strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and Sc treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and Sc revealed at least 1-2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development. (C) 2014 Elsevier Inc. All rights reserved.
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- 2014
10. Extracellular Calcium Modulates Actions of Orthosteric and Allosteric Ligands on Metabotropic Glutamate Receptor 1α
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Jason Y. Jiang, Mulpuri Nagaraju, Jenny J. Yang, P. Jeffrey Conn, Edward M. Brown, Randy A. Hall, Donald Hamelberg, Li Zhang, and Rebecca C. Meyer
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Agonist ,Allosteric modulator ,medicine.drug_class ,Allosteric regulation ,Glycine ,Mutation, Missense ,Pharmacology ,Receptors, Metabotropic Glutamate ,Benzoates ,Biochemistry ,Allosteric Regulation ,Excitatory Amino Acid Agonists ,medicine ,Extracellular ,Humans ,Calcium Signaling ,Receptor ,Molecular Biology ,Binding Sites ,Chemistry ,Glutamate receptor ,Quisqualic Acid ,Cell Biology ,Protein Structure, Tertiary ,HEK293 Cells ,Amino Acid Substitution ,Xanthenes ,Metabotropic glutamate receptor ,Biophysics ,Calcium ,Carbamates ,Molecular Biophysics ,Intracellular - Abstract
Metabotropic glutamate receptor 1α (mGluR1α), a member of the family C G protein-coupled receptors, is emerging as a potential drug target for various disorders, including chronic neuronal degenerative diseases. In addition to being activated by glutamate, mGluR1α is also modulated by extracellular Ca(2+). However, the underlying mechanism is unknown. Moreover, it has long been challenging to develop receptor-specific agonists due to homologies within the mGluR family, and the Ca(2+)-binding site(s) on mGluR1α may provide an opportunity for receptor-selective targeting by therapeutics. In the present study, we show that our previously predicted Ca(2+)-binding site in the hinge region of mGluR1α is adjacent to the site where orthosteric agonists and antagonists bind on the extracellular domain of the receptor. Moreover, we found that extracellular Ca(2+) enhanced mGluR1α-mediated intracellular Ca(2+) responses evoked by the orthosteric agonist l-quisqualate. Conversely, extracellular Ca(2+) diminished the inhibitory effect of the mGluR1α orthosteric antagonist (S)-α-methyl-4-carboxyphenylglycine. In addition, selective positive (Ro 67-4853) and negative (7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester) allosteric modulators of mGluR1α potentiated and inhibited responses to extracellular Ca(2+), respectively, in a manner similar to their effects on the response of mGluR1α to glutamate. Mutations at residues predicted to be involved in Ca(2+) binding, including E325I, had significant effects on the modulation of responses to the orthosteric agonist l-quisqualate and the allosteric modulator Ro 67-4853 by extracellular Ca(2+). These studies reveal that binding of extracellular Ca(2+) to the predicted Ca(2+)-binding site in the extracellular domain of mGluR1α modulates not only glutamate-evoked signaling but also the actions of both orthosteric ligands and allosteric modulators on mGluR1α.
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- 2014
11. Toward Determining ATPase Mechanism in ABC Transporters
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Yan Zhou, Mulpuri Nagaraju, Jingzhi Pu, and Pedro Ojeda-May
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0301 basic medicine ,biology ,ATPase ,Ab initio ,ATP-binding cassette transporter ,Potential energy ,QM/MM ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Membrane ,chemistry ,ATP hydrolysis ,Computational chemistry ,biology.protein ,Biological system ,Adenosine triphosphate - Abstract
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are ubiquitous ATP-dependent membrane proteins involved in translocations of a wide variety of substrates across cellular membranes. To understand the chemomechanical coupling mechanism as well as functional asymmetry in these systems, a quantitative description of how ABC transporters hydrolyze ATP is needed. Complementary to experimental approaches, computer simulations based on combined quantum mechanical and molecular mechanical (QM/MM) potentials have provided new insights into the catalytic mechanism in ABC transporters. Quantitatively reliable determination of the free energy requirement for enzymatic ATP hydrolysis, however, requires substantial statistical sampling on QM/MM potential. A case study shows that brute force sampling of ab initio QM/MM (AI/MM) potential energy surfaces is computationally impractical for enzyme simulations of ABC transporters. On the other hand, existing semiempirical QM/MM (SE/MM) methods, although affordable for free energy sampling, are unreliable for studying ATP hydrolysis. To close this gap, a multiscale QM/MM approach named reaction path-force matching (RP-FM) has been developed. In RP-FM, specific reaction parameters for a selected SE method are optimized against AI reference data along reaction paths by employing the force matching technique. The feasibility of the method is demonstrated for a proton transfer reaction in the gas phase and in solution. The RP-FM method may offer a general tool for simulating complex enzyme systems such as ABC transporters.
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- 2016
12. Molecular Cycloencapsulation Augments Solubility and Improves Therapeutic Index of Brominated Noscapine in Prostate Cancer Cells
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Ritu Aneja, Mulpuri Nagaraju, Vijay K. Rangari, Mohamed O. Abdalla, Donald Hamelberg, Timothy Turner, Jitender Madan, Clayton Yates, and Bharat Baruah
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Male ,Noscapine ,Magnetic Resonance Spectroscopy ,Cell Survival ,Stereochemistry ,Pharmaceutical Science ,Dioxoles ,Article ,Differential scanning calorimetry ,X-Ray Diffraction ,In vivo ,Cell Line, Tumor ,Spectroscopy, Fourier Transform Infrared ,Drug Discovery ,medicine ,Humans ,Moiety ,Fourier transform infrared spectroscopy ,Solubility ,Cyclodextrins ,Calorimetry, Differential Scanning ,Chemistry ,Prostatic Neoplasms ,Nuclear magnetic resonance spectroscopy ,Isoquinolines ,Stability constants of complexes ,Molecular Medicine ,Nuclear chemistry ,medicine.drug - Abstract
We have previously shown that a novel microtubule-modulating noscapinoid, EM011 (9-Br-Nos), displays potent anticancer activity by inhibition of cellular proliferation and induction of apoptosis in prostate cancer cells and preclinical mice models. However, physicochemical and cellular barriers encumber the development of viable formulations for future clinical translation. To circumvent these limitations, we have synthesized EM011-cyclodextrin inclusion complexes to improve solubility and enhance therapeutic index of EM011. Phase solubility analysis indicated that EM011 formed a 1:1 stoichiometric complex with β-CD and methyl-β-CD, with a stability constant (K(c)) of 2.42 × 10(-3) M and 4.85 × 10(-3) M, respectively. Fourier transform infrared spectroscopy suggested the penetrance of either a O-CH(2) or OCH(3)-C(6)H(4)-OCH(3) moiety of EM011 in the β-CD or methyl-β-CD cavity. In addition, multifarious techniques, namely, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, NMR spectroscopy, and computational studies validated the cage complex of EM011 with β-CD and methyl-β-CD. Moreover, rotating frame overhauser enhancement spectroscopy showed that the H(a) proton of the OCH(3)-C(6)H(4)-OCH(3) moiety was in close proximity with H3 proton of the β-CD or methyl-β-CD cavity. Furthermore, we found that the solubility of EM011 in phosphate buffer saline (pH 7.4) was enhanced by ~11 fold and ~21 fold upon complexation with β-CD and methyl-β-CD, respectively. The enhanced dissolution of the drug CD-complexes in aqueous phase remarkably decreased their IC(50) to 28.5 μM (9-Br-Nos-β-CD) and 12.5 μM (9-Br-Nos-methyl-β-CD) in PC-3 cells compared to free EM011 (~200 μM). This is the first report to demonstrate the novel construction of cylcodextrin-based nanosupramolecular vehicles for enhanced delivery of EM011 that warrants in vivo evaluation for the superior management of prostate cancer.
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- 2012
13. Active site acidic residues and structural analysis of modelled human aromatase: A potential drug target for breast cancer
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J. Narashima Murthy, G. Narahari Sastry, Mulpuri Nagaraju, A. Raghuram Rao, and G. Madhavi Sastry
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Models, Molecular ,Stereochemistry ,Amino Acids, Acidic ,Breast Neoplasms ,Formestane ,Substrate Specificity ,chemistry.chemical_compound ,Aromatase ,Enzyme Stability ,Drug Discovery ,medicine ,Humans ,Moiety ,Computer Simulation ,Carboxylate ,Physical and Theoretical Chemistry ,Site-directed mutagenesis ,Binding Sites ,biology ,Hydrogen bond ,Aromatization ,Active site ,Computer Science Applications ,chemistry ,Docking (molecular) ,biology.protein ,Female ,medicine.drug - Abstract
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.
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- 2006
14. Cyclodextrin complexes of reduced bromonoscapine in guar gum microspheres enhance colonic drug delivery
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Michelle D. Reid, Ritu Aneja, Bharat Baruah, Timothy Turner, Mulpuri Nagaraju, Donald Hamelberg, Vijay K. Rangari, Sushma R. Gundala, Jitender Madan, and Clayton Yates
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Noscapine ,Pharmaceutical Science ,Infrared spectroscopy ,Beta-Cyclodextrins ,β-cyclodextrin (β-CD) ,Galactans ,Article ,Mannans ,Red-Br-Nos ,Drug Discovery ,Plant Gums ,Spectroscopy, Fourier Transform Infrared ,Moiety ,Humans ,Solubility ,chemistry.chemical_classification ,Cyclodextrins ,Guar gum ,Chromatography ,guar gum microspheres (GGMs) ,Cyclodextrin ,Calorimetry, Differential Scanning ,Chemistry ,beta-Cyclodextrins ,methyl-β-cyclodextrin (methyl-β-CD) ,Microspheres ,colon cancer ,Stability constants of complexes ,Drug delivery ,Molecular Medicine ,cytotoxicity ,HT29 Cells ,Nuclear chemistry - Abstract
Here, we report improved solubility and enhanced colonic delivery of reduced bromonoscapine (Red-Br-Nos), a cyclic ether brominated analogue of noscapine, upon encapsulation of its cyclodextrin (CD) complexes in bioresponsive guar gum microspheres (GGM). Phase-solubility analysis suggested that Red-Br-Nos complexed with β-CD and methyl-β-CD in a 1:1 stoichiometry, with a stability constant (Kc) of 2.29 × 10(3) M(-1) and 4.27 × 10(3) M(-1). Fourier transforms infrared spectroscopy indicated entrance of an O-CH₂ or OCH₃-C₆H₄-OCH₃ moiety of Red-Br-Nos in the β-CD or methyl-β-CD cavity. Furthermore, the cage complex of Red-Br-Nos with β-CD and methyl-β-CD was validated by several spectral techniques. Rotating frame Overhauser enhancement spectroscopy revealed that the Ha proton of the OCH₃-C₆H₄-OCH₃ moiety was closer to the H₅ proton of β-CD and the H₃ proton of the methyl-β-CD cavity. The solubility of Red-Br-Nos in phosphate buffer saline (PBS, pH ∼ 7.4) was improved by ∼10.7-fold and ∼21.2-fold when mixed with β-CD and methyl-β-CD, respectively. This increase in solubility led to a favorable decline in the IC₅₀ by ∼2-fold and ∼3-fold for Red-Br-Nos-β-CD-GGM and Red-Br-Nos-methyl-β-CD-GGM formulations respectively, compared to free Red-Br-Nos-β-CD and Red-Br-Nos-methyl-β-CD in human colon HT-29 cells. GGM-bearing drug complex formulations were found to be highly cytotoxic to the HT-29 cell line and further effective with simultaneous continuous release of Red-Br-Nos from microspheres. This is the first study to showing the preparation of drug-complex loaded GGMS for colon delivery of Red-Br-Nos that warrants preclinical assessment for the effective management of colon cancer.
- Published
- 2014
15. Synthesis and selective cytotoxic activity of novel hybrid chalcones against prostate cancer cells
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C. Ashwini, V. Lakshma Nayak, Mulpuri Nagaraju, Sistla Ramakrishna, Rajesh Chandra, E. Gnana Deepthi, B.B. Gawali, and M.V.P.S. Vishnuvardhan
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Male ,Colorectal cancer ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Biochemistry ,Prostate cancer ,Mice ,Structure-Activity Relationship ,Chalcone ,Cell Line, Tumor ,Drug Discovery ,medicine ,Cytotoxic T cell ,Structure–activity relationship ,Animals ,Humans ,Spectral analysis ,Lung cancer ,Molecular Biology ,Chemistry ,Organic Chemistry ,Prostatic Neoplasms ,medicine.disease ,Molecular biology ,Cell culture ,Proton NMR ,Molecular Medicine ,Drug Screening Assays, Antitumor - Abstract
A new class of hybrid chalcones (17a-l &18a-l) was synthesized by Claisen-Schmidt condensation. All compounds were characterized by (1)H NMR, IR and mass spectral analysis and tested for their cytotoxic activity against PC-3 (prostate cancer), HT-29 (colon cancer), B-16 (mouse macrophages) and NCI-H460 (lung cancer) cell lines. Three compounds 18i, 18j and 18l (IC(50)=8.4, 7.9 & 5.9 μM) showed significant activity against PC-3 cell line.
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- 2012
16. Disease Related Mutations Adjacent to Predicted Multiple Ca2+ Binding Sites of Ca2+-Sensing Receptor Altering Intracellular Ca2+ Oscillations via Extracellular Calcium and Amino Acid Signaling
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Chen Zhang, Edward M. Brown, Fadil M. Hannan, Mulpuri Nagaraju, Yusheng Jiang, Jenny J. Yang, Donald Hamelberg, Yun Huang, and Rajesh V. Thakker
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chemistry.chemical_classification ,Biophysics ,chemistry.chemical_element ,Calcium ,Biology ,Calcium in biology ,Cell biology ,Amino acid ,chemistry ,Biochemistry ,Extracellular ,Amino acid binding ,Calcium-sensing receptor ,Intracellular ,G protein-coupled receptor - Abstract
Calcium sensing receptor (CaSR), along other members of the family C G protein-coupled receptors (GPCRs), play very important roles in responding to changes in the extracellular calcium concentrations and in circulating levels of amino acids and integrating these extracellular signals into alterations in intracellular signaling pathways. We have reported several potential calcium-binding sites located within the CaSR's extracellular domain using our developed computational algorithms. In the present study, we first report the differential effects of several disease-related mutations located at the predicted calcium binding sites on the inhibition and activation of intracellular calcium responses using single cell imaging. Interestingly, mutating to different residues at two locations near the hinge region of the ECD could lead to either significantly lose of function of the receptor or gain of function (switch function mutations). Amino acid binding results in differential rescue effect in altering intracellular calcium responses, especially calcium oscillations. We further analyzed the effect of mutation and amino acid binding on the correlation motion, cooperativity, and synergistic activation use computational methods. These results provide important implications for our understanding of how the CaSR integrates information about these two completely different classes of agonists--an inorganic divalent cation, and another hand, a nutrient-- how the receptor senses these agonists in healthy and diseased states.
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- 2012
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17. Effect of alkyl substitution on H-bond strength of substituted amide-alcohol complexes
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Mulpuri Nagaraju and G. Narahari Sastry
- Subjects
chemistry.chemical_classification ,Models, Molecular ,Electron density ,Hydrogen ,Molecular Structure ,Hydrogen bond ,Organic Chemistry ,chemistry.chemical_element ,Alcohol ,Hydrogen Bonding ,Photochemistry ,Acceptor ,Amides ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,chemistry.chemical_compound ,Crystallography ,Computational Theory and Mathematics ,chemistry ,Amide ,Alcohols ,Molecule ,Physical and Theoretical Chemistry ,Alkyl - Abstract
The effect of alkyl substitution (CH3, C2H5, n-C3H7, i-C3H7, and t-C4H9) on the hydrogen bond strengths (H-bond) of substituted amide-alcohol complexes has been systematically explored. B3LYP/aug-cc-pVDZ method was applied to a total of 215 alkyl substituted amide-alcohol complexes to delineate the effect of substitution on the H-bond strength; formamide-water complex is taken as reference point. Complexes are classified into five types depending on the hydrogen donor, acceptor and the site of alkyl substitution (Type-IA, Type-IIA, Type-IB, Type-IIB and Type-III). The strength of H-bond was correlated with geometrical parameters such as proton-acceptor (H∙∙∙∙Y) distance, the length of proton donating bond (X–H). In all the complexes N–H and O–H stretching frequencies are red-shifted. The effect of alkyl substitution on N–H and O–H stretching frequencies were analyzed. Topological parameters like electron density at H∙∙∙∙Y and X–H bond critical points as derived from atom in molecules (AIM) theory was also evaluated. When C = O group is participating in H-bond, the strength of H-bond decreases with increasing size of alcohols except for methanol (Type-IA, Type-III and Type-IB complexes). But it increases with increasing size of alkyl groups on amide and decreases with bulky groups. In the case of N–H group as H-bond donor, the strength of H-bond increases with increasing size of alcohols (Type-IIA and Type-IIB complexes) whereas decreases with increasing size of alkyl groups on amide. Type-IA, IIA, IB and IIB complexes exhibit good correlations among IE, H-bond distance and electron density at bcp. In Type-III complexes, average H-bond distance and sum of electron densities shows better correlation with IEs than the corresponding individuals. The correlation of IE less with electron density at RCP compared to sum of electron densities.
- Published
- 2010
18. Role of Ca2+ and L-Phe in Regulating Functional Cooperativity of Disease-Associated “Toggle” Calcium-Sensing Receptor Mutations
- Author
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Zhang, Chen, primary, Mulpuri, Nagaraju, additional, Hannan, Fadil M., additional, Nesbit, M. Andrew, additional, Thakker, Rajesh V., additional, Hamelberg, Donald, additional, Brown, Edward M., additional, and Yang, Jenny J., additional
- Published
- 2014
- Full Text
- View/download PDF
19. Formation of linear polymers with pendant vinyl groups via inclusion complex mediated polymerization of divinyl monomers
- Author
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Satav, Sunita S., Karmalkar, Rohini N., Kulkarni, Mohan G., and Mulpuri, Nagaraju
- Subjects
Chemistry - Abstract
A demonstration that, in the polymerization of divinyl monomers, the double bond included in the cyclodextrins (CD) cavity does not react with the growing radical chain is presented. This results in soluble, linear polymers containing pendant vinyl unsaturations.
- Published
- 2006
20. Theoretical studies on inclusion complexes of cyclodextrins
- Author
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G. Narahari Sastry and Mulpuri Nagaraju
- Subjects
Quantum chemical ,chemistry.chemical_compound ,Molecular dynamics ,Cyclodextrins ,Molecular Structure ,Chemistry ,Computational chemistry ,Molecule ,Quantum Theory ,Physical and Theoretical Chemistry ,Molecular Dynamics Simulation ,Benzene ,Small molecule - Abstract
Quantum chemical calculations and molecular dynamics simulations are carried out to study the host-guest inclusion complexes of cyclodextrins (alpha-, beta-, and gamma-CDs) with small guest molecules such as H(2)O, NH(3), NH(4)(+), C(6)H(6), and bisimidazolyl compounds. The uptake ability of the CDs to accommodate the small molecules inside the cavity is examined by the sequential addition of 10 molecules of water or ammonia using the semiempirical (PM3) method. In the case of benzene, this was done up to six molecules. PM3 calculations indicate that alpha-, beta-, and gamma-CD can accommodate three, seven, and nine water molecules, respectively. In the case of NH(3) as guest molecule, alpha-, beta-, and gamma-CDs can accommodate up to two, five, and six molecules, respectively. Semiempirical calculations indicate that two benzene molecules can be accommodated in the alpha-CD cavity, whereas beta- and gamma-CD cavities adopt three and four benzene molecules, respectively. Molecular dynamics simulations were carried out for 1.0 ns on benzene and bisimidazolyl complexes of CDs in explicit solvent (TIP3P water model). The interaction energies calculated by the MM/PBSA method reveal that ligand 1,6-bis(imidazol-l-lyl) hexane (B) and 1,4-bis(imidazol-l-lylmethyl) benzene (C) molecules prefer to form 1:1 complexes with alpha-, beta-, and gamma-CDs. However, C preferentially forms 1:2 complexes with alpha-CDs. Ligands 1,10-bis(imidazol-l-lyl) decane (A) and 4,4'-(bis(imidazol-l-ylmethylene))biphenyl (D) form 1:2 complexes with alpha-, beta-, and gamma-CDs in head-to-head (HH) orientation of CDs. The stability of inclusion compounds depends on the type of CD and the physicochemical properties of the involved guest. Both of these methods (semiempirical and MD simulations) reveal that beta-CDs form more stable complexes compared with alpha- and gamma-CDs with C, D, NH(4)(+), and C(6)H(6), whereas alpha-CD forms more stable complexes with A and B.
- Published
- 2009
21. Comparative study on formamide-water complex
- Author
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G. Narahari Sastry and Mulpuri Nagaraju
- Subjects
Formamide ,Range (particle radiation) ,Chemistry ,Hydrogen bond ,Condensed Matter Physics ,Atomic and Molecular Physics, and Optics ,chemistry.chemical_compound ,Computational chemistry ,Ab initio quantum chemistry methods ,Potential energy surface ,Physical chemistry ,Molecule ,Density functional theory ,Physical and Theoretical Chemistry - Abstract
The hydrogen bonding of 1:1 complexes formed between formamide and water molecule have been investigated systematically using Hartree–Fock (HF), hybrid density functional theory (B3LYP), and post-Hartree–Fock (MP2 and CCSD(T)) methods with range of basis sets 6-31G(d), cc-pVXZ (X = D, T, Q) and aug-cc-pVYZ (Y = D, T). Three stable structures are considered on the potential energy surface of formamide and water system. The optimized geometric parameters and interaction energies for various isomers at different levels are estimated. The IR frequencies, intensities, and frequency shifts are reported. This study shows that B3LYP/aug-cc-pVDZ method gives better performance for formamide-water complexes. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010.
- Published
- 2009
22. Identification of an l-Phenylalanine Binding Site Enhancing the Cooperative Responses of the Calcium-sensing Receptor to Calcium
- Author
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Zhang, Chen, primary, Huang, Yun, additional, Jiang, Yusheng, additional, Mulpuri, Nagaraju, additional, Wei, Ling, additional, Hamelberg, Donald, additional, Brown, Edward M., additional, and Yang, Jenny J., additional
- Published
- 2014
- Full Text
- View/download PDF
23. Hetero Interaction with an Amino Acid Globally Enhances Cooperative Activation of CaSR in Response to Extracellular Signaling
- Author
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Zhang, Chen, primary, Zhuo, You, additional, Feng, Jie, additional, Strachan, Heather, additional, Mulpuri, Nagaraju, additional, Hamelberg, Donald, additional, Moremen, Kelley, additional, Brown, Edward M., additional, and Yang, Jenny J., additional
- Published
- 2013
- Full Text
- View/download PDF
24. Hydrogen Bonding in Trivinyl Monomers: Implications for Inclusion Complexation and Polymerization
- Author
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Satav, Sunita S., primary, Karmalkar, Rohini N., additional, Kulkarni, Mohan G., additional, Mulpuri, Nagaraju, additional, and Sastry, G. Narahari, additional
- Published
- 2007
- Full Text
- View/download PDF
25. Role of Ca2+ and L-Phe in Regulating Functional Cooperativity of Disease-Associated “Toggle” Calcium-Sensing Receptor Mutations.
- Author
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Zhang, Chen, Mulpuri, Nagaraju, Hannan, Fadil M., Nesbit, M. Andrew, Thakker, Rajesh V., Hamelberg, Donald, Brown, Edward M., and Yang, Jenny J.
- Subjects
- *
CALCIUM ions , *CALCIUM-sensing receptors , *GENETIC mutation , *HOMEOSTASIS , *CELLULAR signal transduction - Abstract
The Ca2+-sensing receptor (CaSR) regulates Ca2+ homeostasis in the body by monitoring extracellular levels of Ca2+ ([Ca2+]o) and amino acids. Mutations at the hinge region of the N-terminal Venus flytrap domain (VFTD) produce either receptor inactivation (L173P, P221Q) or activation (L173F, P221L) related to hypercalcemic or hypocalcemic disorders. In this paper, we report that both L173P and P221Q markedly impair the functional positive cooperativity of the CaSR as reflected by [Ca2+]o–induced [Ca2+]i oscillations, inositol-1-phosphate (IP1) accumulation and extracellular signal-regulated kinases (ERK1/2) activity. In contrast, L173F and P221L show enhanced responsiveness of these three functional readouts to [Ca2+]o. Further analysis of the dynamics of the VFTD mutants using computational simulation studies supports disruption in the correlated motions in the loss-of-function CaSR mutants, while these motions are enhanced in the gain-of-function mutants. Wild type (WT) CaSR was modulated by L-Phe in a heterotropic positive cooperative way, achieving an EC50 similar to those of the two activating mutations. The response of the inactivating P221Q mutant to [Ca2+]o was partially rescued by L-Phe, illustrating the capacity of the L-Phe binding site to enhance the positive homotropic cooperativity of CaSR. L-Phe had no effect on the other inactivating mutant. Moreover, our results carried out both in silico and in intact cells indicate that residue Leu173, which is close to residues that are part of the L-Phe-binding pocket, exhibited impaired heterotropic cooperativity in the presence of L-Phe. Thus, Pro221 and Leu173 are important for the positive homo- and heterotropic cooperative regulation elicited by agonist binding. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
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