Discovery of novel quinolinone adenosine A2B antagonists

Published in: Journal, Article, Volume : 20, Issue : 24, Pages : 7414-7420

DOI : 10.1016/j.bmcl.2010.10.030

Author : McGuinness, Brian F.; Ho, Koc-Kan; Stauffer, Tara M.; Rokosz, Laura L.; Mannava, Neelima; Kultgen, Steven G.; Saionz, Kurt; Klon, Anthony; Chen, Weiqing; Desai, Hema; Rogers, W. Lynn; Webb, Maria; Yin, Juxing; Jiang, Yan; Li, Tailong; Yan, Hao; Jing, Konghua; Zhang, Shengting; Majumdar, Kanak Kanti; Srivastava, Vikash; Saha, Samiran

Abstract : A novel series of quinolinone-based adenosine A2B receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A2B antagonist (2i, I) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).

A coumarin based ICT probe for fluoride in aqueous medium with its real application

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 82, Issue : 1, Pages : 312-318

DOI : 10.1016/j.talanta.2010.04.041

Author : Upadhyay, K. K.; Mishra, Rakesh K.; Kumar, Virendra; Chowdhury, P. K. Roy

Abstract : A new coumarin based hydrazone (receptor 1) synthesized by modifying one of our earlier reported receptor detected fluoride ion selectively through naked eye in aqueous DMSO (5:95, volume/volume). It was also able to detect fluoride through naked eye in a toothpaste sample. The addition of 1 equivalent of fluoride as its tetrabutylammonium salt to the 5 × 10-5 M aqueous DMSO solution of the receptor 1 produced red color while the similar addition of acetate produced faint pink color. The dihydrogen phosphate and a variety of other anions were not able to produce any significant color change with receptor 1 under similar exptl. conditions. The corresponding UV-vis measurements showed a bathochromic shifting of 455 nm band of receptor 1 to 514 and 484 nm for fluoride and acetate, resp. The non-linear fittings of corresponding UV-vis titration data in 1:1 binding equation yielded association constants in 105:1 ratio for fluoride and acetate, resp. The 1H NMR titrations studies shade further light on their mode of binding with receptor 1. The quantum mech. calculations through time dependant d. functional theory (TD-DFT) using basis set b3lyp/6-311g** supported our exptl. findings nicely.

Turning a Mesophilic Protein into a Thermophilic One: A Computational Approach Based on 3D Structural Features

Published in: Journal, Article, Volume : 49, Issue : 7, Pages : 1741-1750

DOI : 10.1021/ci900183m

Author : Basu, Sohini; Sen, Srikanta

Abstract : In spite of considerable improvement of our understanding of factors responsible for protein thermostability, rational designing of thermostable variants of mesophilic proteins is not yet fully established. The present paper describes an effective computational strategy that we have developed to identify the most suitable mutations converting a chosen mesophilic protein into a thermophilic one starting from its 3D structure. The approach is based on the concept that stabilization of several surface residues should enhance the global stability of the protein. The method relies on the estimation of electrostatic and van der Waals interactions in computing the interaction among the side chains of individual residues and the rest of the protein. The polar or charged residues whose side chains interact weakly with the rest of the original protein are identified first. Then, for each such identified residue (A), another residue (B) in its spatial vicinity is identified. The side chain of the residue (B) is then replaced by a suitable conformer of a residue that is electrostatically complementary to the residue (A) to enhance local interactions and hence the stability of the protein. The steric effect is taken care of through van der Waals interactions. We reject the mutations that improve interactions only locally along the sequence as it is unlikely to enhance the global stability of the 3D architecture. We use the difference in self-energies (ΔEself) as a measure of the stability difference between the original and its mutant variant. This paper presents two test cases with demonstration of the enhanced stability of such mutated proteins and validates the strategy by considering five exptl. known thermophilic-mesophilic protein pairs.

A new chalcone glycoside from Rhamnus nipalensis

Published in: Journal, Article, Volume : 22, Issue : 18, Pages : 1657-1659

DOI : 10.1080/14786410701876635

Author : Pandey, M. B.; Singh, A. K.; Singh, U.; Singh, S.; Pandey, V. B.

Abstract : A new chalcone glycoside, chalcone-2′,4-dihydroxy-4′-O-β-D-glucoside was isolated from Rhamnus nipalensis together with sitosterol, lupeol, di-O-methyldaidzein, kaempferol-4′-methylether, quercetin, physcion, sitosterol glucoside, emodin and their structures established by spectroscopic data. Isolation of these compounds are the first report from this plant.

Synthetic and spectroscopic studies of some new 2-[1-aryl-4{4-methoxyphenyl}-6-thioxo-1,6-dihydro-1,3,5-triazinyl]amino/ hydrazonothiazolidin-4-ones

Published in: Journal, Volume : 45, Issue : 3, Pages : 741-744

DOI : 10.1002/jhet.5570450317

Author : Roychowdhuary, P. K.; Upadhay, K. K.; Mishra, Rakesh K.; Kumar, Ajit; Mehrotra, Sangeeta; Srivastava, Sugandh; Upadhyay, Shalini

Abstract : A series of 4-thiazolidinones having triazinethione moieties have been synthesized by the systematic chem. modification of S-benzylmercapto-1-aryl-4-(4-methoxyphenyl)-1,6-dihydro-1,3,5-triazine-6-thione.

Cyclopeptide alkaloids from Zizyphus sativa bark

Published in: Journal, Article, Volume : 22, Issue : 3, Pages : 219-221

DOI : 10.1080/14786410601133483

Author : Pandey, Manoj Bhushan; Singh, Ashok Kumar; Singh, Virendra Pratap; Pandey, Vidya Bhushan

Abstract : A new cyclopeptide alkaloid, sativanine-M, together with known alkaloid nummularine-P were isolated from the stem bark of Zizyphus sativa and identified by spectral anal.

Exploring the potential of complex formation between a mutant DNA and the wild type protein counterpart: A MM and MD simulation approach

Published in: Journal, Article, Volume : 25, Issue : 1, Pages : 158-168

DOI : 10.1016/j.jmgm.2005.11.004

Author : Roy, Sujata; Sen, Srikanta

Abstract : We have demonstrated that the methods of mol. modeling and mol. dynamics simulation might be used to assess whether a specific mutation in the DNA would destabilize a known DNA-protein complex. The approach is based on probing the changes in the interaction that would be induced into the complex if within the already formed wild type complex the mutation could be introduced. We have used Hoxc8-DNA complex as a test system where it is known that the Hoxc8 binding affinity of the DNA is completely lost upon mutation of the DNA by replacing TAAT stretch to GCCG. Mutation was obtained by changing the relevant base pairs into the DNA of the model of the corresponding wild type complex developed by homol. modeling and MD simulation in water for 2.0 ns. Comparison of the structure, dynamics and interactions between the hypothetical mutant model with those of the similarly refined wild type model shows that the loss of affinity of the mutant DNA to Hoxc8 has two different origins: (i) loss of several strong H-bonds as the direct consequences of mutation and (ii) reduced H-bonds in the common parts due to a net loss or inferior H-bonding geometry induced by the mutation as indirect effects. The net change in the interaction energy between the DNA and the protein in the best possible configuration indicated the exptl. observed destabilization effects. No significant change in the groove width was observed and no correlation was found between the water-bridges and the loss of affinity.

Design and synthesis of potent non-peptidic inhibitors of HPTPβ

Published in: Journal, Article, Volume : 16, Issue : 16, Pages : 4252-4256

DOI : 10.1016/j.bmcl.2006.05.074

Author : Amarasinghe, Kande K. D.; Evidokimov, Artem G.; Xu, Kevin; Clark, Cynthia M.; Maier, Matthew B.; Srivastava, Anil; Colson, Anny-Odile; Gerwe, Gina S.; Stake, George E.; Howard, Brian W.; Pokross, Matthew E.; Gray, Jeffrey L.; Peters, Kevin G.

Abstract : The sulfamic acid phosphotyrosine mimetic was coupled with a previously known malonate template to obtain highly selective and potent inhibitors of HPTPβ. Potentially hydrolyzable malonate ester functionalities were replaced with 1,2,4-oxadiazoles without a significant effect on HPTPβ potency.

A Simple Approach for Indexing the Oral Druglikeness of a Compound: Discriminating Druglike Compounds from Nondruglike Ones

Published in: Journal, Article, Volume : 46, Issue : 3, Pages : 1394-1401

DOI : 10.1021/ci050459i

Author : Biswas, Dhrubajyoti; Roy, Sujata; Sen, Srikanta

Abstract : A knowledge-based simple score has been developed for indexing the oral druglikeness of compounds based on the concept that oral druglikeness should be independent of the drug targets and, thus, are closely related to the global absorption, distribution, metabolism, and excretion related properties. We have considered several simple mol. descriptors as the key determinants of druglikeness. The patterns of the distributions of these mol. descriptors for a set of drug mols. have been extracted using a nonlinear neural network method. We assumed direct correlations of these patterns to the expectation values that a given compound may behave like a drug. On the basis of this assumption, we have defined a simple druglike index or score (DLS) combining the contributions coming from the descriptors considered. This index scales the druglikeness of a compound in the range 0.0-1.0, 1.0 being the highest druglikeness. The index applied for a drug data set, a mixed data set, and three different bioactive databases produced expected features and indicated that even the marketed drugs have druglike scores varying over a considerable range. A total of 73.3% of the drugs considered showed DLS > 0.5, while it is only 44.7% for the HIC-Up compounds (unbiased ligand database). For the ChemBank, Asinex-Gold collection, and NCI databases 61.2%, 76.0%, and 79.1% of the compounds have DLS > 0.5.

One-pot synthesis of 1,2,4-oxadiazoles from carboxylic acid esters and amidoximes using potassium carbonate

Published in: Journal, Volume : 47, Issue : 22, Pages : 3629-3631

DOI : 10.1016/j.tetlet.2006.03.155

Author : Amarasinghe, Kande K. D.; Maier, Matthew B.; Srivastava, Anil; Gray, Jeffrey L.

Abstract : A convenient one-pot synthesis of 1,2,4-oxadiazoles is described. The condensation of carboxylic acid esters and amidoximes in the presence of potassium carbonate was employed to synthesize a variety of mono-, bis- and tris-oxadiazoles in moderate to excellent yields.