A comparative study of Shilajatu and Asanadi Ghana Vati in the management of Madhumeha w.s.r. to type-2 diabetes mellitus.

INTRODUCTION: Diabetes mellitus is becoming an alarming problem for society nowadays causing impediment in normal life. Diabetes and its complications impose a major burden upon health-care facilities. MATERIALS AND METHODS: In this study, 90 patients of Madhumeha (type-2 diabetes mellitus) were registered and randomly divided into two groups. Out of 90 registered patients, 80 patients completed the treatment. In Group A, cap. Shilajatu (500 mg twice daily) was given for 3 months and in Group B, Asanadi Ghana Vati (2 Vati twice daily) was given for 3 months. AIM: An attempt was made to evaluate and compare the efficacy of Shilajatu and Asanadi Ghana Vati in the management of type-2 diabetes mellitus. The efficacy of therapy was assessed on the basis of improvement in sign and symptoms of diabetes mellitus, blood sugar level, and glycosylated hemoglobin. RESULTS: Statistically significant improvement was observed in sign and symptoms as well as on blood sugar level in both groups after the completion of treatment. CONCLUSION: Shilajatu and Asanadi Ghana Vati seem to be effective and completely safe for the management of Madhumeha (type-2 diabetes mellitus).

Rational design, synthesis, and crystallographic analysis of a hydroxyethylene-based HIV-1 protease inhibitor containing a heterocyclic P1'--P2' amide bond isostere.

The rational design and synthesis of a highly potent inhibitor of HIV-1 protease have been accomplished. The inhibitor, SB 206343, is based on a model derived from the structure of the MVT-101/HIV-1 protease complex and contains a 4(5)-acylimidazole ring as an isosteric replacement for the P1'--P2' amide bond. It is a competitive inhibitor with an apparent inhibition constant of 0.6 nM at pH 6.0. The three-dimensional structure of SB 206343 bound in the active site of HIV-1 protease has been determined at 2.3 A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel Fo magnitude of/Fc parallel/sigma magnitude of), of 0.194. The inhibitor is held in the enzyme by a set of hydrophobic and polar interactions. N-3 of the imidazole ring participates in a novel hydrogen-bonding interaction with the bound water molecule, demonstrating the effectiveness of the imidazole ring as an isosteric replacement for the P1'--P2' amide bond in hydroxyethylene-based HIV-1 protease inhibitors. Also present are hydrogen-bonding interactions between N-1 of the imidazole ring and the carbonyl of Gly-127 as well as between the imidazole acyl carbonyl oxygen and the amide nitrogen of Asp-129, exemplifying the peptidomimetic nature of the 4(5)-acylimidazole isostere. All of these interactions are in qualitative agreement with those predicted by the model.

Clinical evaluation of Kushmanda Ghrita in the management of depressive illness.

Depressive illness has been considered as a problematic mental illness since antiquity. The treatment modalities of depressive illness are of many kinds. Use of Medhya Rasayana drugs is a unique method of treatment described in Ayurveda for depressive illness. Kushmanda (Benincasa hispida) is one of the Medhya Rasayana as described by Bhava Mishra. Ghrita is also considered as Medhya Rasayana by almost all Acharyas. Keeping this background Kushmanda Ghrita has been selected as a trial drug to treat the patients of depressive illness. The study was carried out in 35 clinically diagnosed cases of depressive illness by using DSM-IV diagnostic criteria of depressive illness. All patients were given 20 ml of Kushmanda Ghrita in two divided doses morning and evening with 40 ml of lukewarm water for a period of one month. It has shown statistically significant results with psychometric parameters-Hamilton depression rating scale (t = 24.36, P < 0.001), Hamilton anxiety rating scale (t = 26.20, P < .001), immediate memory span direct (t = 4.35, P < 0.001), and indirect test (t = 3.43, P < 01) along with clinical symptoms.

A perspective for susruta samhita.

A suggestion was made recently that the account of dissection of the cadaver present in Susruta Samhita is probably not in the true tradition of Ayurveda and the art of dissection itself is presumably of the Greek origin. By a closer scrutiny of the Text and its internal evidence, it has been shown here that this contention is likely to be not only incorrect but also unwarranted. In this connection a rather new perspective, which may probably be better than usual to evaluate the Samita itself is posited.

The crystal structures at 2.2-A resolution of hydroxyethylene-based inhibitors bound to human immunodeficiency virus type 1 protease show that the inhibitors are present in two distinct orientations.

As part of a structure-based drug design program directed against enzyme targets in the human immunodeficiency virus (HIV), we have determined the three-dimensional structures of the HIV type 1 protease complexed with two hydroxyethylene-based inhibitors. The inhibitors (SKF 107457 and SKF 108738) are hexapeptide substrate analogues with the scissile bond being replaced by a hydroxyethylene isostere. The structures were determined using x-ray diffraction data to 2.2 A measured at the Cornell High Energy Synchrotron Source on hexagonal crystals of each of the complexes. The structures have been extensively refined using a reciprocal space least-squares method to conventional crystallographic R factors of 0.186 and 0.159, respectively. The protein structure differs from that in the unliganded state of the enzyme and is most similar to that of the structure of the other reported (Jaskolski, M., Tomasselli, A. G., Sawyer, T. K., Staples, D. G., Heinrikson, R. L., Schneider, J., Kent, S. B. H., and Wlodawer, A. (1990) Biochemistry 29, 5889-5907) hydroxyethylene-based inhibitor complex. Unlike in that structure, however, the inhibitors are observed, in the present crystal structures, in two equally abundant orientations that are a consequence of the homodimeric nature of the enzyme coupled with the asymmetric structures of the inhibitors. Although the differences between the two inhibitors used in the present study are confined to the P1' site, the van der Waals interactions made by the inhibitor atoms with the amino acid residues in the protein differ throughout the structures of the inhibitors.

Preliminary crystallization studies of calmodulin-dependent protein phosphatase (calcineurin) from bovine brain.

Calcineurin is a serine/threonine protein phosphatase which catalyzes the hydrolysis of both phosphoseryl/phosphothreonyl and phosphotyrosyl proteins as well as low molecular weight compounds such as p-nitrophenyl phosphate. It is a hetero-dimeric protein consisting of a 60 kDa A chain and 19 kDa B chain. Calcineurin A is organized into functionally distinct domains such as a catalytic domain, a calcineurin B binding domain, a calmodulin-binding domain, and an inhibitory domain. Calcineurin B has four EF-hand calcium binding domains with a secondary structure that is homologous to calmodulin but its metal binding properties are more similar to troponin-C. The N-terminal myristoyl group of calcineurin B might play a role in the interaction between subunits A and B during phosphorylation/dephosphorylation processes. Crystals of size 0.125 x 0.07 x 0.03 mm and 0.7 x 0.03 x 0.02 mm have been obtained for calcineurin and the A subunit respectively. Crystals of calcineurin show strong diffraction to 5.3 A and weak diffraction to 3.0 A on rotating anode operated at 50 kV and 100 mA. Further work is in progress to improve the X-ray diffraction quality of these crystals and to obtain well diffracting crystals of calcineurin B.

RETRACTED: Crystal structure of a complement control protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of request of the editors. Cell is retracting this paper reporting structures of a poxvirus protein, VCP, that inhibits the complement system. The paper presents a structural model derived from two crystal forms of the protein (PDB: 1G40 and 1G44) that defines an interaction surface implicated in inhibition of complement C3 proteins and visualizes heparin binding sites. We were contacted by the University of Alabama, Birmingham (UAB), the corresponding author's institution, with a report detailing concerns about the veracity of the structures and recommending that the structures be retracted from the Protein Data Bank. We then conducted an assessment with input from experts in the field who found that the structures as presented in the paper were not consistent with available data, including spatial packing and structure (B) factors. These findings were consistent with issues contained in the UAB report. A subsequent investigation by the Department of Health and Human Services Office of Research Integrity (https://www.federalregister.gov/documents/2018/04/16/2018-07782/findings-of-research-misconduct) has concluded that the corresponding author, Krishna H.M. Murthy, engaged in research misconduct and that the structures were falsified and/or fabricated. Given the results of our own assessment and the institutional investigations, the most appropriate course of action is to retract the paper. Co-authors Nick Mullin, Paul N. Barlow, and Craig M. Ogata support this retraction.

Inhibition of human immunodeficiency virus-1 protease by a C2-symmetric phosphinate. Synthesis and crystallographic analysis.

The human immunodeficiency virus type 1 (HIV-1) protease is a potential target of acquired immune deficiency syndrome (AIDS) therapy. A highly potent, perfectly symmetrical phosphinate inhibitor of this enzyme, SB204144, has been synthesized. It is a competitive inhibitor of HIV-1 protease, with an apparent inhibition constant of 2.8 nM at pH 6.0. The three-dimensional structure of SB204144 bound to the enzyme has been determined at 2.3-A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel F(o) magnitude to - Fc parallel/sigma magnitude of F(o)), of 0.178. The inhibitor is held in the enzyme active site by a set of hydrophobic and hydrophilic interactions, including an interaction between Arg8 and the center of the terminal benzene rings of the inhibitor. The phosphinate establishes a novel interaction with the two catalytic aspartates; each oxygen of the central phosphinic acid moiety interacts with a single oxygen of one aspartic acid, establishing a very short (2.2-2.4 A) oxygen-oxygen contact. As with the structures of penicillopepsin bound to phosphinate and phosphonate inhibitors [Fraser, M. E., Strynadka, N. C., Bartlett, P. A., Hanson, J. E., & James, M. N. (1992) Biochemistry 31, 5201-14], we interpret this short distance and the stereochemical environment of each pair of oxygens in terms of a hydrogen bond that has a symmetric single-well potential energy curve with the proton located midway between the two atoms.(ABSTRACT TRUNCATED AT 250 WORDS)

An orally bioavailable HIV-1 protease inhibitor containing an imidazole-derived peptide bond replacement: crystallographic and pharmacokinetic analysis.

(2R,4S,5S,1'S)-2-Phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl) amino-6-phenylhexanoyl-N-(1'-imidazo-2-yl)-2'-methylpropanamide (compound 2) is a tripeptide analogue inhibitor of HIV-1 protease in which a C-terminal imidazole substituent constitutes an isoelectronic, structural mimic of a carboxamide group. Compound 2 is a potent inhibitor of the protease (K(i) = 18 nM) and inhibits HIV-1 acute infectivity of CD4+ T-lymphocytes (IC50 = 570 nM). Crystallographic analysis of an HIV-1 protease-compound 2 complex demonstrates that the nitrogen atoms of the imidazole ring assume the same hydrogen-bonding interactions with the protease as amide linkages in other peptide analogue inhibitors. The sole substitution of the C-terminal carboxamide of a hydroxyethylene-containing tripeptide analogue with an imidazole group imparts greatly improved pharmacokinetic and oral bioavailability properties on the compound compared to its carboxamide-containing homologue (compound 1). While the oral bioavailability of compound 1 in rats was negligible, compound 2 displayed oral bioavailabilities of 30% and 14%, respectively, in rats and monkeys.