Krishna Misra

Design, synthesis and characterization of some bioactive conjugates of curcumin with glycine, glutamic acid, valine and demethylenated piperic acid and study of their antimicrobial and antiproliferative properties

The monoesters of curcumin, a symmetric diphenol with valine and glycine have been prepared by a novel solid phase synthesis and its diesters with valine, glutamic acid and demethylenated piperic acid have been prepared by solution phase method. The assessment of their antimicrobial and anticancer (antiproliferative) activities suggested that diesters of curcumin are relatively more active than curcumin itself due to their increased solubility, slow metabolism and better cellular uptake. Furthermore, significant observation was that monoesters of curcumin have even better antimicrobial activity than their corresponding diesters, emphasizing the role of free phenolic group. The conjugate of curcumin with demethylenated piperic acid in which methylenedioxy ring was open also shows enhanced activity than the corresponding piperic acid conjugate, emphasizing the role of free phenolics in the transport or in the binding processes.

Computational screening of molecular targets in Plasmodium for novel non resistant anti-malarial drugs

Histone acetyltransferase (HAT) is an enzyme required for chromatin remodeling and transcriptional activation. Sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) is an ATP coupled Ca2+ ion pump involved in metabolic arrest. Both these enzymes are present in Plasmodia and have been selected as molecular targets for in silico studies of some new non-resistant antimalarial drugs like artemisinin, curcumin and diarylheptanoids along with some other inhibitors reported in literature. Ten top inhibitors have also been generated based on common pharmacophore from ZINC database. The HAT enzyme was modeled with the help of the Modeller software and the SERCA enzyme pdb file was obtained from the protein data bank. Ligbuilder was used for structure based drug designing, which generated a common pharmacophore of the ligands. Molegro was used to perform virtual screening of the hits from the pharmacophore based Zinc database search and known inhibitors of the enzymes from the literature survey. Curcumin shows good and optimal binding to both HAT and SERCA enzymes; therefore it might be a good inhibitor of these key enzymes in Plasmodium. Curcumin is reported to act synergistically with artemisinin which forms covalent adducts with the transmembrane proteins (SERCA enzyme) and inactivates them, thus inhibiting the activity of Plasmodium parasite. This combination has already been reported to be effective in malaria treatment. Some other diarylheptanoids besides curcumin showed better binding to both the enzymes. Therefore, a combination of artemisinin and diarylheptanoids can prove to be better combination for antimalarial therapy. Different formulations involving curcumin, artimisinin and diarylheptanoids may result in a more potent antimalarial drug.

Towards the interaction mechanism of tocopherols and tocotrienols (vitamin E) with selected metabolizing enzymes.

Vitamin E is a mixture of eight compounds α, β, γ, δ tocopherols and α, β, γ, δ tocotrienols. Their individual role in cellular transport as antioxidants and in metabolic pathways has been highlighted in the present work. All the eight compounds have been docked with the respective metabolizing enzymes (αtocopherol transfer protein (ATTP), αtocopherol associated protein (TAP), Pglycoprotein (Pgly) and human serum albumin (HSA)) to understand molecular interactions for pharmacokinetics. These have been structurally aligned against the four human phospholipids in order to reveal their individual role in chylomicron formation and hence the mechanism of cellular transport. The study of their binding with their metabolizing enzymes provides insight to the comparative antioxidant activity of each of these isomers.

Contact depigmentation caused by an azo dye in alta

Alta, a scarlet‐red solution used by some Indian women as a cosmetic to colour their feet, was found to be associated with depigmentation at the site of application. Chromatographic and spectroscopic analysis of 3 brands of alta confirmed the presence of 2 dyes: Crocein Scarlet MOO (CSM) (brilliant crocein) and rhodamine B (tetraethyl rhodamine). Patch testing produced depigmentation at the site of application of alta, CSM and para‐phenylenediamine (PPD). Although PPD has been reported to produce leukoderma, azo dyes have not previously been reported as depigmenting agents.

Human papilloma virus 16 e6 protein as a target for curcuminoids, curcumin conjugates and congeners for chemoprevention of oral and cervical cancers

Curcumin (diferuloyl methane) and its naturally occurring analogs viz. demethoxy, bisdemethoxy and cyclocurcumin, present in rhizomes of curcuma species turmeric, have been shown to inhibit the proliferation of a wide variety of tumor cells. Target nuclear protein HPV 16 E6 (PDB ID: 2fk4) is the major protein actively participating in oral and cervical cancers. In silico studies indicate that curcumin and its natural analogs have effective binding with different active sites on HPV 16 E6 protein, ideal target for restoring the tumor suppressor function of p53 and thus allowing the apoptosis of infected cells. The main limitation in the use of curcuminoids as therapeutic agents is their low bioavailability. Since piperine is known to enhance curcumin bioavailability to more than two thousand times by inhibiting its efflux, a conjugate of curcumin-piperic acid was also used. Although curcumin has been found to have strongest binding with this target and the two curcuminoids, demethoxy and bisdemethoxy curcumin have lower but comparable affinity, chlorogenic acid amongst the naturally occurring analogs has been found to have best binding affinity amongst all the analogs. Although curcumin-piperoyl conjugate does not show very encouraging results, it is likely to have potential activity in vitro and in vivo. These results throw light on the SAR of curcuminoids, leading to future designing of potent, non-toxic drugs for oral and cervical cancers.

Modeling and simulation analysis of propyl-thiouracil (PTU), an anti-thyroid drug on thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide (NIS) symporter based on systems biology approach

The aim of metabolic modeling was to understand the cause effect interaction and reliance linked with the complex interactions of biological networks and molecular systems. Drugs that therapeutically modulate the biological processes of disease are often developed with limited knowledge of the underlying complexity of their specific targets. The robustness for systemic modulating behavior of thyroid hormone secretion during the course of different time unit simulation is explained in this study. In this work, a computational model has been developed which mimics the in vivo simulation. The model was constructed with the help of cell designer 4.1 used for analyzing the effect of perturbed amount of drugs at 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 amounts as a unit, targeting Thyroid Peroxidase (TPO), Thyroid Stimulating Hormone Receptor (TSHR), and Sodium Iodide Symporter (NIS). The rate kinetic equations were defined with each reaction to simulate the molecular species dynamic behavior. The modulating behavior of thyroid hormone secretion was analyzed by the process of activation and inactivation states of TPO, TSHR, and NIS at various amounts of drugs. Obtained results explain suitably the entire observable fact of the drug effects and are capable to proceed in response to the perturbations of the natural cell. TSHR was found as the most potent molecular therapeutic target in this study.

Identification of epitopes in Indian human papilloma virus 16 E6: a bioinformatics approach.

HPV-16 is reported as the cause of cervical and other related carcinomas. The early expressed protein E6 in cancer cells is found to be the target for immune therapeutic methods. The sequence of HPV-16 E6 (Accession No: ABK32509) from NCBI databank has been taken for this study. Hydrophilicity, flexibility, accessibility, turns, exposed surface, polarity and antigenic propensity scales were used for the B cell epitope prediction. MHC Class I and Class II alleles for the accession were predicted by the MHCPred 2.0 Program. The epitope sequences were also found out. Computer-based prediction program results show, A0203 and DRB0101 lower IC50 than other alleles. The best peptide binding affinity was 21HLCTELQTT30 of A0203 allele. In DRB0101 allele the peptide found was 39YCKQQLLRR48. Different structural features of the protein have also been predicted including glycosylation, kinase C phosphorylation, casein kinase II phosphorylation and N-myristylation sites. These computational prediction programs show four glycosylation, five kinase C phosphorylation, two casein kinase II phosphorylation, zero N-myristylation sites and seven disulphide sites. Development and approval of new vaccines are the keys for control of cancer. Epitopes and other structural features of protein prediction could be the best source of information and can help in molecular and medical studies of viral infection and development of HPV associated cancer drugs.

A comparative study on the molecular descriptors for predicting drug-likeness of small molecules.

Screening of “ drug-like” molecule from the molecular database produced through high throughput techniques and their large repositories requires robust classification. In our work, a set of heuristically chosen nine molecular descriptors including four from Lipinskis rule, were used as classification parameter for screening “drug-like” molecules. The robustness of classification was compared with four fundamental descriptors of Lipinski. Back propagation neural network based classifier was applied on a database of 60000 molecules for classification of, “ drug-like” and “non drug-like” molecules. Classification result using nine descriptors showed high classification accuracy of 96.1% in comparison to that using four Lipinskis descriptors which yielded an accuracy of 82.48%. Also a significant decrease of false positives resulted while using nine descriptors causing a sharp 18% increase of specificity of classification. From this study it appeared that Lipinskis descriptors which mainly deal with pharmacokinetic properties of molecules form the basis for identification of “drug-like” molecules that can be substantially improved by adding more descriptors representing pharmacodynamics properties of molecules.

Curcuminoids as inhibitors of thioredoxin reductase: a receptor based pharmacophore study with distance mapping of the active site.

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzyme responsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to compare the potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results show that active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded by distance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 from C13 of demethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at least one methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites of the TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probable potent antiproliferative synthetic drugs.

Occupational and systemic contact dermatitis with photosensitivitydue to vitamin B6

Keywords: pyridoxine hydrochloride; vitamin B6; contact hypersensitivity; systemic contact dermatitis; occupational; cutaneous adverse drug reaction; photosensitivity; paramedical worker; health care workers; medicaments