Target prioritization of novel substituted 5-aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-triones as anticancer agents using in-silico approach

Abstract

Cancer is a multi-origin collection of diseases attributed by abnormal and uncontrolled cell growth spread from origin to other parts of body eventually leading to death. After decades of research, anticancer drug therapy is still very much limited to inhibiting growth and controlling the spread of tumour cells. Finding novel molecular targets and drug candidates using assimilation of experimental and computational approaches is among the recent strategies adopted by researchers to speed up the anticancer drug discovery process. In present study, synthesis of 40 novel substituted 5-aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-triones has been accomplished followed by molecular target identification using different in silico approaches. The target prioritization methodology involved identification and selection of targets, molecular docking followed by molecular dynamic simulation and determination of binding free energy using MM-GBSA technique. Systematic and stepwise virtual screening of biological targets lead to identification of B-cell lymphoma 6 protein (BCL6), lysine-specific histone demethylase 1?A (LSD1), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB P65) and poly (ADP-ribose) polymerase 1 (PARP1) as suitable anticancer targets for the set of synthesized compounds.

Communicated by Ramaswamy H. Sarma     

Breeding habitat and nest-site selection of Bearded Vulture Gypaetus barbatus in the Annapurna Himalaya Range of Nepal

Quantitative studies on nesting habitat selection are important to understand and predict the resource requirements for breeding habitat. In this study, we analysed nest-site (cliff) and territory selection patterns of the Bearded Vulture in the Annapurna Range of the Himalayas (Nepal). Our study area represents high-elevation mountain range systems, where information on nest selection is lacking, despite having the largest remaining populations of Bearded Vultures in the world. Our models indicated selection patterns at both nest and territory spatial scales that are consistent with previous studies at lower altitudes (Pyrenees, the Caucasus), such as a preference for landscape patches with greater food availability. However, our models also indicated selection patterns that are probably a response to the higher altitudes and sheer reliefs of the Annapurna massif, such as avoidance of the steepest slopes and selection of cliffs facing south and west for nest-sites. We did not detect an impact of human activities on the distribution of nests or territories. However, the Annapurna massif is experiencing development of infrastructures (e.g. road construction). Further research efforts will be needed to monitor human impacts on Bearded Vulture populations in the Annapurna Range, as this is a global stronghold for this species.     

Giant Extra-Ordinary Near Infrared Transmission from Seemingly Opaque Plasmonic Metasurface: Sensing Applications

Plasmonics - In the present study, we report giant extra-ordinary transmission of near infrared (NIR) light, more than 90%, through a seemingly opaque plasmonic metasurface, which consists of two...     

Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies

The recently reported “UK variant” (B.1.1.7) of SARS-CoV-2 is thought to be more infectious than previously circulating strains as a result of several changes, including the N501Y mutation. We present a 2.9-Å resolution cryo-electron microscopy (cryo-EM) structure of the complex between the ACE2 receptor and N501Y spike protein ectodomains that shows Y501 inserted into a cavity at the binding interface near Y41 of ACE2. This additional interaction provides a structural explanation for the increased ACE2 affinity of the N501Y mutant, and likely contributes to its increased infectivity. However, this mutation does not result in large structural changes, enabling important neutralization epitopes to be retained in the spike receptor binding domain. We confirmed this through biophysical assays and by determining cryo-EM structures of spike protein ectodomains bound to 2 representative potent neutralizing antibody fragments.