Resolution Agonist 15-epi-Lipoxin A Programs Early Activation of Resolving Phase in Post-Myocardial Infarction Healing.

Following myocardial infarction (MI), overactive inflammation remodels the left ventricle (LV) leading to heart failure coinciding with reduced levels of 15-epi-Lipoxin A (15-epi LXA). However, the role of 15-epi LXA in post-MI acute inflammatory response and resolving phase is unclear. We hypothesize that liposomal fusion of 15-epi-LXA (Lipo-15-epi-LXA) or free 15-epi-LXA will expedite the resolving phase in post-MI inflammation.

Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia.

Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that activate the vitamin D receptor (VDR), but are devoid of hypercalcemia. A lead compound (known as VDR 4-1) demonstrated potent transcriptional activities in a VDR reporter gene assay, and significantly ameliorated cardiac hypertrophy in cell culture studies and in animal models.

Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders.

Alterations in sodium flux (I) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel Na1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1).

Discovery of small molecule inhibitors to Krüppel-like factor 10 (KLF10): implications for modulation of T regulatory cell differentiation.

The Krüppel-like family of transcription factors (KLFs) constitute a subfamily of C2H2-type zinc finger proteins with distinct cell-type expression patterns and regulate functional aspects of cell growth and differentiation, activation, or development. KLF10 has been previously shown to critically regulate the acquisition of CD4+CD25+ T regulatory cell differentiation and function, an effect important to the maintenance of self-tolerance, immune suppression, and tumor immunosurveillance. To date, there are no selective pharmacological inhibitors to KLF10.

Comparative Occupancy Analysis (CoOAn) - A Straightforward and Directly Applicable 3D-QSAR Formalism to Extract Molecular Features Obligatory for Designing Potent Leads.

A simple and directly applicable 3D-QSAR method, termed Comparative Occupancy Analysis (CoOAn), has been developed. The method is based on the comparison of local occupancies of fragments of an aligned set of molecules in a 3D-grid space. The formalism commendably extracts the crucial position-specific molecular features and correlates them quantitatively to their biological endpoints.

Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.

Background: Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (<32 weeks) preeclampsia.

Withanolide A and asiatic acid modulate multiple targets associated with amyloid-beta precursor protein processing and amyloid-beta protein clearance.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease histochemically characterized by extracellular deposits of amyloid beta (Abeta) protein and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is considered to be a complex, multifactorial syndrome, with numerous causal factors contributing to its pathogenesis. Thus, for any novel therapeutic molecule to have a "disease-modifying" effect on AD, it must be able to modulate multiple, synergistic targets simultaneously.

Local indices for similarity analysis (LISA)-a 3D-QSAR formalism based on local molecular similarity.

A simple quantitative structure activity relationship (QSAR) approach termed local indices for similarity analysis (LISA) has been developed. In this technique, the global molecular similarity is broken up as local similarity at each grid point surrounding the molecules and is used as a QSAR descriptor. In this way, a view of the molecular sites permitting favorable and rational changes to enhance activity is obtained.

Successful applications of computer aided drug discovery: moving drugs from concept to the clinic.

Drug discovery and development is an interdisciplinary, expensive and time-consuming process. Scientific advancements during the past two decades have changed the way pharmaceutical research generate novel bioactive molecules. Advances in computational techniques and in parallel hardware support have enabled in silico methods, and in particular structure-based drug design method, to speed up new target selection through the identification of hits to the optimization of lead compounds in the drug discovery process.

Binding of lipoic acid induces conformational change and appearance of a new binding site in methylglyoxal modified serum albumin.

The binding of lipoic acid (LA), to methylglyoxal (MG) modified BSA was studied using isothermal titration calorimetry in combination with enzyme kinetics and molecular modelling. The binding of LA to BSA was sequential with two sites, one with higher binding constant and another comparatively lower. In contrast the modified protein showed three sequential binding sites with a reduction in affinity at the high affinity binding site by a factor of 10.

A comprehensive analysis of the thermodynamic events involved in ligand-receptor binding using CoRIA and its variants.

Quantitative Structure-Activity Relationships (QSAR) are being used since decades for prediction of biological activity, lead optimization, classification, identification and explanation of the mechanisms of drug action, and prediction of novel structural leads in drug discovery. Though the technique has lived up to its expectations in many aspects, much work still needs to be done in relation to problems related to the rational design of peptides. Peptides are the drugs of choice in many situations, however, designing them rationally is a complicated task and the complexity increases with the length of their sequence.

CoMFA study of distamycin analogs binding to the minor-groove of DNA: a unified model for broad-spectrum activity.

A 3D-QSAR analysis has been carried out by comparative molecular field analysis (CoMFA) on a series of distamycin analogs that bind to the DNA of drug-resistant bacterial strains MRSA, PRSP and VSEF. The structures of the molecules were derived from the X-ray structure of distamycin bound to DNA and were aligned using the Database alignment method in Sybyl. Statistically significant CoMFA models for each activity were generated.

Design of inhibitors of the MurF enzyme of Streptococcus pneumoniae using docking, 3D-QSAR, and de Novo design.

The biosynthetic pathway for formation of the bacterial cell wall (peptidoglycan) presents an attractive target for intervention. This is exploited by many of the clinically useful antibiotics, which inhibit enzymes involved in the later stages of peptidoglycan synthesis. MurF is one of the four amide bond-forming enzymes (d-alanyl-d-alanine ligating enzyme) that catalyzes the ATP-dependent formation of UDP-MurNAc-tripeptide.

Pharmacophore modeling in drug discovery and development: an overview.

Pharmacophore mapping is one of the major elements of drug design in the absence of structural data of the target receptor. The tool initially applied to discovery of lead molecules now extends to lead optimization. Pharmacophores can be used as queries for retrieving potential leads from structural databases (lead discovery), for designing molecules with specific desired attributes (lead optimization), and for assessing similarity and diversity of molecules using pharmacophore fingerprints.

The B(OH)-NH Analog Is a Surrogate for the Amide Bond (CO-NH) in Peptides: An ab Initio Study.

The conformational preferences of N-methyl-methylboronamide (NMB), a B(OH)-NH analog of the amide CO-NH in natural peptides, have been investigated at the Hartree-Fock; Becke's three-parameter exchange functional and the gradient-corrected functional of Lee, Yang, and Parr; and second-order Møller-Plesset levels of theory with the 6-31+G* basis set. The minima, saddle points, and rotation barriers on the potential energy surface of NMB have been located and the energy barriers estimated. Besides the global minimum, there are three local minima within 2.

Stationary Points on the PES of N-Methoxy Peptides and Their Boron Isosteres: An Ab Initio Study.

The conformational space of N-methoxy-N-methylacetamide [CH3-CO-N(OCH3)CH3, NMA-NOM] and its boron isostere [CH3-CO-B(OCH3)CH3, BMA-BOM] has been studied at the HF, B3LYP, and MP2 levels of theory with the 6-31+G* basis set. The minima, saddle points, and rotation barriers on the PES of these molecules have been located, and the energy barriers estimated. The omega rotation barrier is relatively lower in the boron isostere than in NMA-NOM.

Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands.

A novel approach termed comparative residue-interaction analysis (CoRIA), emphasizing the trends and principles of QSAR in a ligand-receptor environment has been developed to analyze and predict the binding affinity of enzyme inhibitors. To test this new approach, a training set of 36 COX-2 inhibitors belonging to nine families was selected. The putative binding (bioactive) conformations of inhibitors in the COX-2 active site were searched using the program DOCK.

The ω, φ, and ψ Space of N-Hydroxy-N-methylacetamide and N-Acetyl-N '-hydroxy-N '-methylamide of Alanine and Their Boron Isosteres.

The conformational space of N-hydroxy-N-methylacetamide [CH3-CO-N(OH)CH3, NMAOH] and its boron isostere [CH3-CO-B(OH)CH3, BMAOH] has been studied by quantum chemical methods. The potential energy surface of NMAOH and BMAOH has been built at the HF, B3LYP, and MP2 levels of theory with the 6-31+G* basis set. The minima and transition states for rotations about various torsional angles have been located, and the energy barriers have been estimated.

Comparative protein modeling of methionine S-adenosyltransferase (MAT) enzyme from Mycobacterium tuberculosis: a potential target for antituberculosis drug discovery.

Mycobacterium tuberculosis (Mtb) is a successful pathogen that overcomes the numerous challenges presented by the immune system of the host. In the last 40 years few anti-TB drugs have been developed, while the drug-resistance problem is increasing; there is thus a pressing need to develop new anti-TB drugs active against both the acute and chronic growth phases of the mycobacterium. Methionine S-adenosyltransferase (MAT) is an enzyme involved in the synthesis of S-adenosylmethionine (SAM), a methyl donor essential for mycolipid biosynthesis.