Polyamines and its analogue modulates amyloid fibrillation in lysozyme: A comparative investigation.

Background: Polyamines can induce protein aggregation that can be related to the physiology of the cellular function. Polyamines have been implicated in protein aggregation which may lead to neuropathic and non neuropathic amyloidosis.

Scope Of Review: Change in the level of polyamine concentration has been associated with ageing and neurodegeneration such as Parkinson's disease, Alzheimer's disease.

Cross-talk between allosteric and orthosteric binding sites of γ-amino butyric acid type A receptors (GABA-Rs): A computational study revealing the structural basis of selectivity.

The γ-amino butyric acid type A receptors (GABA-Rs) are GABA-gated chloride ion channels that mediate fast inhibitory neurotransmissions. Due to their essential role in normal brain function, neuromodulatory therapies are targeted at them for restoring GABA-mediated inhibition. The receptor modulation by benzodiazepine (BZD) shows therapeutically useful actions.

Enhanced basepair dynamics pre-disposes protein-assisted flips of key bases in DNA strand separation during transcription initiation.

Localized separation of strands of duplex DNA is a necessary step in many DNA-dependent processes, including transcription and replication. Little is known about how these strand separations occur. The strand-separated E.

Aristolochic acid and its derivatives as inhibitors of snake venom L-amino acid oxidase.

Snake venom L-amino acid oxidase (LAAO) exerts toxicity by inducing hemorrhage, pneumorrhagia, pulmonary edema, cardiac edema, liver cell necrosis etc. Being well conserved, inhibitors of the enzyme may be synthesized using the template of the substrate, substrate binding site and features of the catalytic site of the enzyme. Previous findings showed that aristolochic acid (AA), a major constituent of Aristolochia indica, inhibits Russell's viper venom LAAO enzyme activity since, AA interacts with DNA and causes genotoxicity, derivatives of this compound were synthesized by replacing the nitro group to reduce toxicity while retaining the inhibitory potency.

Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads.

Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1.

Computational analysis of BACE1-ligand complex crystal structures and linear discriminant analysis for identification of BACE1 inhibitors with anti P-glycoprotein binding property.

More than 100 years of research on Alzheimer's disease didn't yield a potential cure for this dreadful disease. Poor Blood Brain Barrier (BBB) permeability and P-glycoprotein binding of BACE1 inhibitors are the major causes for the failure of these molecules during clinical trials. The design of BACE1 inhibitors with a balance of sufficient affinity to the binding site and little or no interaction with P-glycoproteins is indispensable.

Identification of novel hits as highly prospective dual agonists for mu and kappa opioid receptors: an integrated in silico approach.

Opioid agonists are used clinically for the treatment of acute and chronic pain, however, their clinical use is limited due to the presence of undesired side effects. Dual agonists, simultaneously targeting mu and kappa opioid receptors, show fewer side effects than that of selective agonists. In the present work, 2D- and 3D- Quantitative Structure Activity Relationship studies were performed on a series of aminomorphinan derivatives as dual agonists, using a wide range of descriptors.

Integration of ligand and structure based approaches for identification of novel MbtI inhibitors in Mycobacterium tuberculosis and molecular dynamics simulation studies.

Mycobacterium tuberculosis is an obligate pathogen of mammals and is responsible for more than two million deaths annually. The ability to acquire iron from the extracellular environment is a key determinant of pathogenicity in mycobacteria. M.

Molecular Shape Analysis-Guided Virtual Screening Platform for Adenosine Kinase Inhibitors.

We propose a new application of molecular shape descriptors in hierarchical selection during virtual screening (VS). Here, a structure-based pharmacophore and docking-guided VS protocol have been evolved to identify inhibitors against adenosine kinase (AK). The knowledge gained on the shape requirements has been extrapolated in classifying active and inactive molecules against this target.

Structural and thermodynamic analysis of the binding of tRNA(phe) by the putative anticancer alkaloid chelerythrine: Spectroscopy, calorimetry and molecular docking studies.

The interaction of the putative anticancer alkaloid chelerythrine with tRNA(phe) was characterized by spectroscopy, calorimetry and molecular docking studies. The charged iminium form of chelerythrine binds with tRNA(phe) in a cooperative mode with a binding affinity value of (4.06±0.

Structure-based designing of sordarin derivative as potential fungicide with pan-fungal activity.

Fungal infections have become a significant problem for immunosuppressed patients. Sordarin, a promising fungicidal agent, inhibits fungal protein synthesis by impairing elongation factor-2 (eEF2) function. Intriguingly, despite high sequence similarity among eEF2s from different species, sordarin has been shown to inhibit translation specifically in certain fungi while unable to do so in some other fungal species (e.

Capturing state-dependent dynamic events of GABAA-receptors: a microscopic look into the structural and functional insights.

The γ-amino butyric acid type A receptors (GABAA-Rs) are the key players in the mammalian brain that meditate fast inhibitory neurotransmission events. The structural integrity of these ligand-gated ion channel controls chloride ion permeability, which in turn monitors important pharmacological functions. Despite ample studies on GABAA-Rs, there was a need for a study on full-length receptor structures, devoted to track structure-function correlations based on their dynamic behavior consideration.

Evaluation of anti-diabetic and alpha glucosidase inhibitory action of anthraquinones from Rheum emodi.

Rheum emodi is used as a culinary plant across the world and finds an eminent role in the Ayurvedic and traditional Chinese systems of medicine. The plant is known to principally contain 1,8-dihydroxyanthraquinones (DHAQs) like rhein, aloe emodin, emodin, chrysophanol and physcion that possess diverse pharmacological and therapeutic actions. The present work deals with developing a platform technology for isolation of these DHAQs and evaluating their anti-diabetic potential.

Chelerythrine-lysozyme interaction: spectroscopic studies, thermodynamics and molecular modeling exploration.

The binding of the iminium and alkanolamine forms of chelerythrine to lysozyme (Lyz) was investigated by spectroscopy and docking studies. The thermodynamics of the binding was studied by calorimetry. Spectroscopic evidence suggested that Trp-62 and Trp-63 in the β-domain of the protein are closer to the binding site; moreover, the binding site was at a distance of 2.

Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening.

BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors.

In silico work flow for scaffold hopping in Leishmania.

Background: Leishmaniasis,a broad spectrum of diseases caused by several sister species of protozoa belonging to family trypanosomatidae and genus leishmania , generally affects poorer sections of the populace in third world countries. With the emergence of strains resistant to traditional therapies and the high cost of second line drugs which generally have severe side effects, it becomes imperative to continue the search for alternative drugs to combat the disease. In this work, the leishmanial genomes and the human genome have been compared to identify proteins unique to the parasite and whose structures (or those of close homologues) are available in the Protein Data Bank.

Binding of the iminium and alkanolamine forms of sanguinarine to lysozyme: spectroscopic analysis, thermodynamics, and molecular modeling studies.

Sanguinarine (SGR) exists in charged iminium (SGRI) and neutral alkanolamine (SGRA) forms. The binding of these two forms to the protein lysozyme (Lyz) was investigated by fluorescence, UV-vis absorbance and circular dichroism spectroscopy, and in silico molecular docking approaches. Binding thermodynamics were studied by microcalorimetry.

3D-QSAR studies and shape based virtual screening for identification of novel hits to inhibit MbtA in Mycobacterium tuberculosis.

Mycobacterium tuberculosis, the pathogen responsible for tuberculosis, uses various strategies to survive in a variety of host lesions. The re-emergence of multi-drug-resistant strains of M. tuberculosis underlines the necessity to discover new molecules.

Functional compensation of glutathione S-transferase M1 (GSTM1) null by another GST superfamily member, GSTM2.

The gene for glutathione-S-transferase (GST) M1 (GSTM1), a member of the GST-superfamily, is widely studied in cancer risk with regard to the homozygous deletion of the gene (GSTM1 null), leading to a lack of corresponding enzymatic activity. Many of these studies have reported inconsistent findings regarding its association with cancer risk. Therefore, we employed in silico, in vitro, and in vivo approaches to investigate whether the absence of a functional GSTM1 enzyme in a null variant can be compensated for by other family members.

14-Deoxyandrographolide targets adenylate cyclase and prevents ethanol-induced liver injury through constitutive NOS dependent reduced redox signaling in rats.

Chronic alcoholism is one of the most common causes of liver diseases worldwide. Nitric oxide (NO) has been proposed to have potential for clinical application against chronic hepatocellular injuries. However, mechanisms underlying hepatoprotective functions of NO in ethanol-induced apoptosis are largely unknown.

Probing the structure of Mycobacterium tuberculosis MbtA: model validation using molecular dynamics simulations and docking studies.

Multidrug resistance capacity of Mycobacterium tuberculosis demands urgent need for developing new antitubercular drugs. The present work is on M. tuberculosis-MbtA, an enzyme involved in the biosynthesis of siderophores, having a critical role in bacterial growth and virulence.

Indirect read-out of the promoter DNA by RNA polymerase in the closed complex.

Transcription is initiated when RNA polymerase recognizes the duplex promoter DNA in the closed complex. Due to its transient nature, the closed complex has not been well characterized. How the initial promoter recognition occurs may offer important clues to regulation of transcription initiation.

Modeling the closed and open state conformations of the GABA(A) ion channel--plausible structural insights for channel gating.

Recent disclosure of high resolution crystal structures of Gloeobacter violaceus (GLIC) in open state and Erwinia chrysanthemii (ELIC) in closed state provides newer avenues to advance our knowledge and understanding of the physiologically and pharmacologically important ionotropic GABA(A) ion channel. The present modeling study envisions understanding the complex molecular transitions involved in ionic conductance, which were not evident in earlier disclosed homology models. In particular, emphasis was put on understanding the structural basis of gating, gating transition from the closed to the open state on an atomic scale.

Rationalizing lead optimization by consensus 2D- CoMFA CoMSIA GRIND (3D) QSAR guided fragment hopping in search of γ-secretase inhibitors.

γ-Secretase (Gamma Secretase) is a potential drug target in Alzheimer's disease therapeutics. A sequel lead design study was undertaken on a series of bicyclononanes with an aim of identifying potent isofunctional chemotypes. Fragment-based bioisosteric replacement, which considers shape, chemistry, and electrostatics was carried out to mine over four million medicinally relevant fragments of Brood database.

Discovery of safe and orally effective 4-aminoquinaldine analogues as apoptotic inducers with activity against experimental visceral leishmaniasis.

Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L.