QSAR Studies and Scaffold Optimization of Predicted Novel ACC 2 Inhibitors to treat Metabolic Syndrome.

BACKGROUND: Metabolic syndrome is one of the major non-communicable global health hazards of the modern world owing to its amplifying prevalence. Acetyl coenzyme-A carboxylase 2 (ACC 2) is one of the most crucial enzymes involved in the manifestation of this disease because of its regulatory role in fatty acid metabolism. OBJECTIVE: To find novel potent ACC 2 inhibitors as therapeutic potential leads for combating metabolic syndrome. METHODS: In the present study, a two-dimensional quantitative structure-activity relationship (2D QSAR) approach was executed on biologically relevant thiazolyl phenyl ether derivatives as ACC 2 inhibitors for structural optimization. The physiochemical descriptors were calculated and thus a correlation was derived between the observed and predicted activity by the regression equation. The significant descriptors i.e. log P (Whole Molecule) and Number of H-bond Donors (Substituent 1) obtained under study were considered for the design of new compounds and their predicted biological activity was calculated from the regression equation of the developed model. The compounds were further validated by docking studies with the prepared ACC 2 receptor. RESULTS: The most promising predicted leads with the absence of an H-bond donor group at the substituted phenyl ether moiety yet increased overall lipophilicity exhibited excellent amino acid binding affinity with the receptor and showed predicted inhibitory activity of 0.0025 µM and 0.0027 µM. The newly designed compounds were checked for their novelty. Lipinski's rule of five was applied to check their druggability and no violation of this rule was observed. CONCLUSION: The compounds designed in the present study have tremendous potential to yield orally active ACC 2 inhibitors to treat metabolic syndrome.

Metabolic Syndrome: The Constellation of Co-morbidities, A Global Threat.

BACKGROUND: Metabolic syndrome, also referred to as Syndrome X or obesity syndrome is a cluster of diseases prevalent worldwide in both developed and developing countries. According to WHO, it is referred to as a pathological condition wherein multiple disorders are manifested in the same individual. These include hypertension, hyperglycemia, dyslipidemia and abdominal obesity. AIMS: Metabolic syndrome is one of the most serious non-communicable health hazards that have gained pivotal importance in the present scenario. The increasing prevalence affecting around 25 % of the world populace, mainly attributes to the acceptance of western culture, i.e. the intake of highcalorie food along with a substantial decrease in manual labor and adoption of sedentary lifestyles. Therefore, its timely prevention and management are the dire need in the present scenario. METHODS: For successful accomplishment of the present review, an exhaustive analysis was performed utilizing a pool of previous related literature. The terms used during the search included 'metabolic syndrome, prevalence, etiology, current pharmacotherapy for metabolic syndrome, etc. PUBMED, Medline and SCOPUS were explored for the study of abstracts, research and review papers in the quest for related data. The articles were downloaded and utilized for a meta-analysis study approach. CONCLUSION: In this review, an attempt was made to apprehend and summarize the epidemiology and treatment strategies for metabolic syndrome with a better understanding of its pathogenesis. It was postulated that an early diagnostic approach and subsequent line of treatment is required to prevent the deterioration of an individual's health and life.

In-silico Studies and Biological Activity of Potential BACE-1 Inhibitors.

BACKGROUND: Alzheimer's disease is a neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in the brain are caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP). OBJECTIVE: The controlled APP processing by inhibition of secretase is the strategy to reduce Aß load to treat Alzheimer's disease. METHODS: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with an activity magnitude greater than 4 of compounds. RESULTS: In the advent of designing new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by the in-silico approach were evaluated by docking interactions. CONCLUSION: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl-substituted carbamate compound exhibited the highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1µM.

Identification of Novel Rho-Kinase-II Inhibitors with Vasodilatory Activity.

Small GTPase protein Rho-kinase (ROCK) plays an important role in the pathogenesis of hypertension. Inhibition of ROCK II brings about the biochemical changes leading to vascular smooth muscles relaxation, finally resulting into potent antihypertensive activity. In the quest for potent ROCK-II inhibitors, a ligand-based pharmacophore containing four essential chemical features, namely two hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), and one hydrophobe (HY), was developed and rigorously validated. The pharmacophore was used for virtual screening, and hits retrieved from the National Cancer Institute (NCI) database were sorted on the basis of fit value, estimate value, and Lipinski's violation. Potential feature interaction of hits was also observed during docking studies with the amino acids present in the active site of Rho-kinase. Based on the above screening, three hits (NSC 2488, NSC 2888, and NSC 4231) were chosen and subjected to in vitro Rho-kinase enzyme-based assay, followed by ex vivo rat aortic vasodilatory assay. All three compounds showed good biological activity as predicted by the model and confirmed by the docking studies.

Chitinases: Therapeutic Scaffolds for Allergy and Inflammation.

BACKGROUND: Chitinases are the evolutionary conserved glycosidic enzymes that are characterized by their ability to cleave the naturally abundant polysaccharide chitin. The potential role of chitinases has been identified in the manifestation of various allergies and inflammatory diseases. In recent years, chitinases inhibitors are emerging as an alluring area of interest for the researchers and scientists and there is a dire need for the development of potential and safe chitinase antagonists for the prophylaxis and treatment of several diseases. OBJECTIVE: The present review expedites the role of chitinases and their inhibitors in inflammation and related disorders. METHODS: At first, an exhaustive survey of literature and various patents available related to chitinases were carried out. Useful information on chitinases and their inhibitor was gathered from the authentic scientific databases namely SCOPUS, EMBASE, PUBMED, GOOGLE SCHOLAR, MEDLINE, EMBASE, EBSCO, WEB OF SCIENCE, etc. This information was further analyzed and compiled up to prepare the framework of the review article. The search strategy was conducted by using queries with key terms " chitin", "chitinase", "chitotrisidase", "acidic mammalian chitinase", "chitinase inhibitors", "asthma" and "chitinases associated inflammatory disorders", etc. The patents were searched using the key terms "chitinases and uses thereof", "chitinase inhibitors", "chitin-chitinase associated pathological disorders" etc. from www.google.com/patents, www.freepatentsonline.com, and www.scopus.com. RESULTS: The present review provides a vision for apprehending human chitinases and their participation in several diseases. The patents available also signify the extended role and effectiveness of chitinase inhibitors in the prevention and treatment of various diseases viz. asthma, acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer. In this regard, extensive pre-clinical and clinical investigations are required to develop some novel, potent and selective drug molecules for the treatment of various inflammatory diseases, allergies and cancers in the foreseeable future. CONCLUSION: In conclusion, chitinases can be used as potential biomarkers in prognosis and diagnosis of several inflammatory diseases and allergies and the design of novel chitinase inhibitors may act as key and rational scaffolds in designing some novel therapeutic agents in the treatment of variety of inflammatory diseases.

In-Silico QSAR Modelling of Predicted Rho Kinase Inhibitors Against Cardio Vascular Diseases.

BACKGROUND: Rho-kinase is an essential downstream target of GTP-binding protein RhoA, and plays a crucial role in the calcium-sensitization pathway. Rho-kinase pathway is critically involved in phosphorylation state of myosin light chain, leading to increased contraction of smooth muscles. Inhibition of this pathway has turned out to be a promising target for several indications such as cardiovascular diseases, glaucoma and inflammatory diseases. METHODS: The present work focuses on a division-based 2D quantitative structure-activity relationship (QSAR) analysis along with a docking study to predict structural features that may be essential for the enhancement of selectivity and potency of the target compounds. Furthermore, a set of indoles and azaindoles were also projected based on the regression equation as novel developments. Molecular docking was applied for exploring the binding sites of the newly predicted set of compounds with the receptor. RESULTS: Results of the docked conformations suggested that introduction of non-bulky and substituted groups in the hinge region of ROCK-II ATP binding pocket would improve the activity by decreasing the bulkiness or length of the compounds. CONCLUSION: ADME studies were performed to ascertain the novelty and drug-like properties of the designed molecules, respectively.

In-Silico Screening of Ligand Based Pharmacophore, Database Mining and Molecular Docking on 2, 5-Diaminopyrimidines Azapurines as Potential Inhibitors of Glycogen Synthase Kinase-3ß.

BACKGROUND: Glycogen synthase kinase-3ß plays a significant role in the regulation of various pathological pathways relating to the Central Nervous System (CNS). Dysregulation of Glycogen synthase kinase 3 (GSK-3) activity gives rise to numerous neuroinflammation and neurodegenerative related disorders that affect the whole central nervous system. OBJECTIVE: By the sequential application of in-silico tools, efforts have been attempted to design the novel GSK-3ß inhibitors. METHOD: Owing to the potential role of GSK-3ß in nervous disorders, we have attempted to develop the quantitative four featured pharmacophore model comprising two Hydrogen Bond Acceptors (HBA), one Ring Aromatic (RA), and one Hydrophobe (HY), which were further affirmed by costfunction analysis, rm2 matrices, internal and external test set validation and Guner-Henry (GH) scoring analysis. Validated pharmacophoric model was used for virtual screening and out of 345 compounds, two potential virtual hits were finalized that were on the basis of fit value, estimated activity and Lipinski's violation. The chosen compounds were subjected to dock within the active site of GSK-3ß. RESULT: Four essential features, i.e., two Hydrogen Bond Acceptors (HBA), one Ring Aromatic (RA), and one Hydrophobe (HY), were subjected to build the pharmacophoric model and showed good correlation coefficient, RMSD and cost difference values of 0.91, 0.94 and 42.9 respectively and further model was validated employing cost-function analysis, rm2-matrices, internal and external test set prediction with r2 value of 0.77 and 0.84. Docked conformations showed potential interactions in between the features of the identified hits (NCI 4296, NCI 3034) and the amino acids present in the active site. CONCLUSION: In line with the overhead discussion, and through our stepwise computational approaches, we have identified novel, structurally diverse glycogen synthase kinase inhibitors.