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14. Correspondence between molecular functionality and crystal structures. Supramolecular chemistry of a family of homologated aminophenols

Author

Vangala, Venu R., Bohgala, Balakrishna R., Dey, Archan, Desiraju, Gautam R., Smith, Philip S., Howard, Judith A.K., Mondal, Raju, Broder, Charlotte K., and Wilson, Chick C.

Subjects
Molecular dynamics -- Research, Crystals -- Structure, Crystals -- Research, Chemistry
Abstract

The crystal structures and packing features of a family of 13 aminophenols, or supraminols, are analyzed and correlated. The findings indicate that even for compounds with complex crystal structures the packing may be reasonably anticipated provided a sufficient number of examples are available.

Published
2003

24. Cytochrome P450 Binding and Bioactivation of Tumor-Targeted Duocarmycin Agents

Author

Bart, Aaron G., Morais, Goreti, Vangala, Venu R., Loadman, Paul M., Pors, Klaus, and Scott, Emily E.

Abstract

Duocarmycin natural products are promising anticancer cytotoxins but too potent for systemic use. Re-engineering of the duocarmycin scaffold has enabled the discovery of prodrugs designed for bioactivation by tissue-specific cytochrome P450 (P450) enzymes. Lead prodrugs bioactivated by both P450 isoforms CYP1A1 and CYP2W1 have shown promising results in xenograft studies; however, to fully understand the potential of these agents it is desirable to compare dual-targeting compounds with isoform-selective analogs. Such redesign requires insight into the molecular interactions with these P450 enzymes. Herein binding and metabolism of the individual stereoisomers of the indole-based duocarmycin prodrug ICT2700 and a nontoxic benzofuran analog ICT2726 were evaluated with CYP1A1 and CYP2W1, revealing differences exploitable for drug design. Although enantiomers of both compounds bound to and were metabolized by CYP1A1, the stereochemistry of the chloromethyl fragment was critical for CYP2W1 interactions. CYP2W1 differentially binds the Senantiomer of ICT2726, and its metabolite profile could potentially be used as a biomarker to identify CYP2W1 functional activity. In contrast to benzofuran-based ICT2726, CYP2W1 differentially binds the Risomer of the indole-based ICT2700 over the Sstereoisomer. Thus the ICT2700 Rconfiguration warrants further investigation as a scaffold to favor CYP2W1-selective bioactivation. Furthermore, structures of both duocarmycin Senantiomers with CYP1A1 reveal orientations correlating with nontoxic metabolites, and further drug design optimization could lead to a decrease of CYP1A1 bioactivation. Overall, distinctive structural features present in the two P450 active sites can be useful for improving P450—and thus tissue-selective—bioactivation.SIGNIFICANCE STATEMENTProdrug versions of the natural product duocarmycin can be metabolized by human tissue-specific cytochrome P450 (P450) enzymes 1A1 and 2W1 to form an ultrapotent cytotoxin and/or high affinity 2W1 substrates to potentially probe functional activity in situ. The current work defines the binding and metabolism by both P450 enzymes to support the design of duocarmycins selectively activated by only one human P450 enzyme.

Published
2022
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26. Crystal structure prediction of aminols: Advantages of a supramolecular synthon approach with experimental structures

Author

Dey, Archan, Howard, Judith A. K., Kirchner, Michael T., Vangala, Venu R., Desiraju, Gautam R., and Mondal, Raju

Subjects
Coordination compounds -- Research, Crystallography -- Research, Amines -- Chemical properties, Chemistry
Abstract

The supramolecular synthon concept recognizes the complexities inherent in crystallization, and the synthon approach to crystal structure prediction (CSP) recognizes that the kinetic issue is not easily resolved with exhaustive computation. It is indicated that as the amount of structural information in crystallographic databases increases, structural prediction is likely to move toward fingerprinting.

Published
2005

30. Spectroscopic (FT-IR, FT-Raman, and 13C SS-NMR) and quantum chemical investigations to provide structural insights into nitrofurantoin–4-hydroxybenzoic acid cocrystals.

Author

Shukla, Anuradha, Khan, Eram, Alsirawan, MHD. Bashir, Mandal, Rajorshi, Tandon, Poonam, and Vangala, Venu R.

Subjects
ATOMS in molecules theory, MOLECULAR structure, RAMAN effect, CHEMICAL properties, NATURAL orbitals, RAMAN spectroscopy
Abstract

Cocrystallization is an attractive approach to improving the physicochemical properties of active pharmaceutical ingredients (APIs), which have great potential in drug development. Accordingly, there is a growing need to understand the physicochemical changes that occur upon co-crystallisation. This work focuses on the combined use of spectroscopy and density functional theory (DFT) calculations to understand the molecular structure, hydrogen bond interactions and physicochemical properties of a pharmaceutical cocrystal. Solid-state NMR (ssNMR) spectroscopy can provide detailed molecular structure information on pharmaceutical cocrystals and complexes. It is non-destructive and usually provides deep structural insights that complement well with vibrational spectroscopy. In this work, a cocrystal of an antibiotic drug, nitrofurantoin (NF), with 4-hydroxybenzoic acid (4HBA) is examined to understand the capability of multiple spectroscopic techniques such as infrared (IR), Raman and solid-state NMR spectroscopies, and to confirm the molecular structure and hydrogen bonding of cocrystal systems. The results of IR and Raman spectroscopy showed that for the cocrystal formation, NF and 4HBA molecules interact through N–H…O–H interactions between the imide N–H of nitrofurantoin and the phenolic –OH of 4-hydroxybenzoic acid, and these interactions are also confirmed by natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses. It is critical to understand whether a given cocrystal, upon conceiving a modified crystalline structure compared to that of its API, shows enhanced physical and chemical properties or not. Computationally, it is found that the NF–4HBA cocrystal shows softer (more reactive) behaviour in comparison to NF as its cocrystal, NF–4HBA, has a low band gap in comparison to the API, NF. These results demonstrate that the quantum chemical approach predicts accurately how to relate cocrystal with its physical and chemical properties. [ABSTRACT FROM AUTHOR]

Published
2019
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34. Study of molecular interactions and chemical reactivity of the nitrofurantoin–3-aminobenzoic acid cocrystal using quantum chemical and spectroscopic (IR, Raman, 13C SS-NMR) approaches.

Author

Shukla, Anuradha, Khan, Eram, Srivastava, Karnica, Sinha, Kirti, Tandon, Poonam, and Vangala, Venu R.

Subjects
MOLECULAR interactions, ANTIBIOTICS, NITROFURANTOIN
Abstract

Investigations of structural reactivity, molecular interactions and vibrational characterization of pharmaceutical drugs are helpful in understanding their behaviour. The aim of this study is to determine the molecular, electronic and chemical properties of the antibiotic drug nitrofurantoin (NF), after cocrystallisation with 3-aminobenzoic acid (3ABA) and to understand how those changes lead to variation of properties in the cocrystal NF–3ABA. NF–3ABA formation is explained by stabilization via the hydrogen-bond network between NF and 3ABA molecules. It is thoroughly characterized by IR, Raman and CP-MAS solid-state 13C NMR techniques, along with quantum chemical calculations. The results of IR, Raman, and 13C NMR analyses showed that imide N–H23 and C12=O of NF interact with the acid C=O and –OH groups in 3-ABA, respectively. Therefore the IR, Raman, and 13C NMR spectra verified the formation of N–H…O and O–H…O hydrogen bonds. To study hydrogen bonding interactions theoretically in NF–3ABA, two functionals B3LYP and wB97X-D have been used. A comparison is made between the results obtained by B3LYP and those predicted at the wB97X-D level. It is found that wB97X-D is best applied density functional theory (DFT) functional to describe the hydrogen bonding interactions. The strength and nature of hydrogen bonding in NF–3ABA have been analysed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. To validate the results obtained by QTAIM theory and to study the long-range forces, such as van der Waals interactions, the steric effects in NF–3ABA, the reduced density gradient (RDG) and the isosurface have been plotted using Multiwfn software. QTAIM and isosurface analysis suggested that the hydrogen bonding interactions present in NF–3ABA are moderate in nature. The calculated HOMO–LUMO energy gap shows that NF–3ABA is more active than NF and 3ABA. Chemical reactivity descriptors are calculated to understand the various aspects of pharmacological sciences. Chemical reactivity parameters show that NF–3ABA is softer and chemically more reactive than NF. The results suggest that cocrystals can be a feasible alternative for positively changing the targeted physicochemical properties of an active pharmaceutical ingredient (API). [ABSTRACT FROM AUTHOR]

Published
2017
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40. Correction for Polymorphs, Salts and Cocrystals: What’s in a Name?

Author

Aitipamula, Srinivasulu, primary, Banerjee, Rahul, additional, Bansal, Arvind K., additional, Biradha, Kumar, additional, Cheney, Miranda L., additional, Choudhury, Angshuman Roy, additional, Desiraju, Gautam R., additional, Dikundwar, Amol G., additional, Dubey, Ritesh, additional, Duggirala, Nagakiran, additional, Ghogale, Preetam P., additional, Ghosh, Soumyajit, additional, Goswami, Pramod Kumar, additional, Goud, N. Rajesh, additional, Jetti, Ram K. R., additional, Karpinski, Piotr, additional, Kaushik, Poonam, additional, Kumar, Dinesh, additional, Kumar, Vineet, additional, Moulton, Brian, additional, Mukherjee, Arijit, additional, Mukherjee, Gargi, additional, Myerson, Allan S., additional, Puri, Vibha, additional, Ramanan, Arunachalam, additional, Rajamannar, T., additional, Reddy, C. Malla, additional, Rodriguez-Hornedo, Nair, additional, Rogers, Robin D., additional, Row, T. N. Guru, additional, Sanphui, Palash, additional, Shan, Ning, additional, Shete, Ganesh, additional, Singh, Amit, additional, Sun, Changquan C., additional, Swift, Jennifer A., additional, Thaimattam, Ram, additional, Thakur, Tejender S., additional, Kumar Thaper, Rajesh, additional, Thomas, Sajesh P., additional, Tothadi, Srinu, additional, Vangala, Venu R., additional, Vishweshwar, Peddy, additional, Weyna, David R., additional, and Zaworotko, Michael J., additional

Published
2012
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41. Polymorphs, Salts, and Cocrystals: What’s in a Name?

Author

Aitipamula, Srinivasulu, primary, Banerjee, Rahul, additional, Bansal, Arvind K., additional, Biradha, Kumar, additional, Cheney, Miranda L., additional, Choudhury, Angshuman Roy, additional, Desiraju, Gautam R., additional, Dikundwar, Amol G., additional, Dubey, Ritesh, additional, Duggirala, Nagakiran, additional, Ghogale, Preetam P., additional, Ghosh, Soumyajit, additional, Goswami, Pramod Kumar, additional, Goud, N. Rajesh, additional, Jetti, Ram R. K. R., additional, Karpinski, Piotr, additional, Kaushik, Poonam, additional, Kumar, Dinesh, additional, Kumar, Vineet, additional, Moulton, Brian, additional, Mukherjee, Arijit, additional, Mukherjee, Gargi, additional, Myerson, Allan S., additional, Puri, Vibha, additional, Ramanan, Arunachalam, additional, Rajamannar, T., additional, Reddy, C. Malla, additional, Rodriguez-Hornedo, Nair, additional, Rogers, Robin D., additional, Row, T. N. Guru, additional, Sanphui, Palash, additional, Shan, Ning, additional, Shete, Ganesh, additional, Singh, Amit, additional, Sun, Changquan C., additional, Swift, Jennifer A., additional, Thaimattam, Ram, additional, Thakur, Tejender S., additional, Kumar Thaper, Rajesh, additional, Thomas, Sajesh P., additional, Tothadi, Srinu, additional, Vangala, Venu R., additional, Variankaval, Narayan, additional, Vishweshwar, Peddy, additional, Weyna, David R., additional, and Zaworotko, Michael J., additional

Published
2012
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