Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane.

Poor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs-withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that whereas withaferin-A, could proficiently transverse through the model membrane, withanone showed weak permeability.

2, 3-Dihydro-3β-methoxy Withaferin-A Lacks Anti-Metastasis Potency: Bioinformatics and Experimental Evidences.

Withaferin-A is a withanolide, predominantly present in Ashwagandha (Withania somnifera). It has been shown to possess anticancer activity in a variety of human cancer cells in vitro and in vivo. Molecular mechanism of such cytotoxicity has not yet been completely understood.

Fragment-Based Ligand Designing.

Fragment-based drug design strategies have been used in drug discovery since it was first demonstrated using experimental structural biology techniques such as nuclear magnetic resonance (NMR) and X-ray crystallography. The underlying idea is that existing or new chemical entities with known desirable properties may serve both as tool compounds and as starting points for hit-to-lead expansion. Despite the recent advancements, there remain challenges to overcome, such as assembly of the synthetically feasible structures, development of scoring functions to correlate structure and their activities, and fine tuning of the promising molecules.

Withaferin-A kills cancer cells with and without telomerase: chemical, computational and experimental evidences.

Maintenance of telomere length is the most consistent attribute of cancer cells. Tightly connected to their capacity to overcome replicative mortality, it is achieved either by activation of telomerase or an Alternative mechanism of Lengthening of Telomeres (ALT). Disruption of either of these mechanisms has been shown to induce DNA damage signalling leading to senescence or apoptosis.

Influence of symmetric and asymmetric alterations of maxillary canine gingival margin on the perception of smile esthetics among orthodontists, dentists, and laypersons.

Introduction: Esthetics is one of the major concerns among people seeking orthodontic treatment, and its perception varies from person to person. Our objective was to determine the differences in the perception of smile esthetics among orthodontists, general dentists, and laypersons with respect to alteration in the maxillary canine gingival margin in close-up smile analyses.

Materials And Methods: Close-up photograph of an ideal Indian female smile was selected.

Mixed Inhibition of cPEPCK by Genistein, Using an Extended Binding Site Located Adjacent to Its Catalytic Cleft.

Cytosolic phosphoenolpyruvate carboxykinase (cPEPCK) is a critical enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis. cPEPCK converts oxaloacetic acid (OAA) into phosphoenol pyruvate (PEP) in the presence of GTP. cPEPCK is known to be associated with type 2 diabetes.

Targeting Mortalin by Embelin Causes Activation of Tumor Suppressor p53 and Deactivation of Metastatic Signaling in Human Breast Cancer Cells.

Embelin, a natural quinone found in the fruits of Embelia ribes, is commonly used in Ayurvedic home medicine for a variety of therapeutic potentials including anti-inflammation, anti-fever, anti-bacteria and anti-cancer. Molecular mechanisms of these activities and cellular targets have not been clarified to-date. We demonstrate that the embelin inhibits mortalin-p53 interactions, and activates p53 protein in tumor cells.

Computational Structure-Based De Novo Design of Hypothetical Inhibitors against the Anti- Inflammatory Target COX-2.

Cyclooxygenase-2 (COX-2) produces prostaglandins in inflamed tissues and hence has been considered as an important target for the development of anti-inflammatory drugs since long. Administration of traditional non-steroidal anti-inflammatory drugs (NSAIDs) and other COX-2 selective inhibitors (COXIBS) for the treat of inflammation has been found to be associated with side effects, which mainly includes gastro-intestinal (GI) toxicity. The present study involves developing a virtual library of novel molecules with high druglikeliness using structure-based de novo drug designing and 2D fingerprinting approach.

Probing the molecular mechanism of hypericin-induced parasite death provides insight into the role of spermidine beyond redox metabolism in Leishmania donovani.

Hypericin, a natural compound from Hypericum perforatum (St. John's wort), has been identified as a specific inhibitor of Leishmania donovani spermidine synthase (LdSS) using integrated computational and biochemical approaches. Hypericin showed in vitro inhibition of recombinant LdSS enzyme activity.

Withanone-rich combination of Ashwagandha withanolides restricts metastasis and angiogenesis through hnRNP-K.

Ashwagandha is an important herb used in the Indian system of traditional home medicine, Ayurveda. Alcoholic extract (i-Extract) from its leaves and its component, withanone, were previously shown to possess anticancer activity. In the present study, we developed a combination of withanone and withaferin A, major withanolides in the i-Extract, that retained the selective cancer cell killing activity and found that it also has significant antimigratory, -invasive, and -angiogenic activities, in both in vitro and in vivo assays.

Molecular interactions of Bcl-2 and Bcl-xL with mortalin: identification and functional characterization.

Bcl-2 family of proteins consists of both pro-apoptotic and anti-apoptotic members that control cellular apoptosis. They predominantly reside in the mitochondria and control the release of apoptotic factors from the mitochondria to the cytosol by regulating its membrane potential and opening the PT (permeability transition) pore. Here we report bioinformatics and biochemical evidence to demonstrate the interaction between Bcl-2 and Bcl-xL with a stress chaperone, mortalin.

Blocking protein kinase C signaling pathway: mechanistic insights into the anti-leishmanial activity of prospective herbal drugs from Withania somnifera.

Background: Leishmaniasis is caused by several species of leishmania protozoan and is one of the major vector-born diseases after malaria and sleeping sickness. Toxicity of available drugs and drug resistance development by protozoa in recent years has made Leishmaniasis cure difficult and challenging. This urges the need to discover new antileishmanial-drug targets and antileishmanial-drug development.

Mechanistic insights into the dual inhibition strategy for checking Leishmaniasis.

Leishmaniasis (1) is an endemic disease mainly caused by the protozoan Leishmania donovani (Ld). Polyamines have been identified as essential organic compounds for the growth and survival of Ld. These are synthesized in Ld by polyamine synthesis pathway comprising of many enzymes such as ornithine decarboxylase (ODC), spermidine synthase (SS), and S-adenosylmethionine decarboxylase.

A leishmaniasis study: structure-based screening and molecular dynamics mechanistic analysis for discovering potent inhibitors of spermidine synthase.

Protozoa Leishmania donovani (Ld) is the main cause of the endemic disease leishmaniasis. Spermidine synthase (SS), an important enzyme in the synthetic pathway of polyamines in Ld, is an essential element for the survival of this protozoan. Targeting SS may provide an important aid for the development of drugs against Ld.

Role of aromatic stack pairing at the catalytic site of gelonin protein.

Aromatic-aromatic interactions play an important role in the enzyme-substrate recognition mechanism and in stabilization of proteins. Gelonin--a ribosome inactivating protein (RIP) from the plant Gelonium multiflorum--belongs to type-I RIPs and shows N-glycosylation activity which has been used as a model to explain the role of aromatic-aromatic stack pairing in RIPs. RIPs have a different substrate binding site and catalytic site.