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Favipiravir and remdesivir are investigational drugs for coronavirus disease 2019 that is caused by severe acute respiratory syndrome coronavirus 2. The active forms of these drugs are reported to target and inhibit viral RNA dependent RNA polymerase, which is derived from 3-chymotrypsin like protease, a viral replicase enzyme. The present in silico study explores the comparative efficacy of these drugs to inhibit 3-chymotrypsin like protease and RNA dependent RNA polymerase, to plan therapeutic options for patients based on their disease severity. Active favipiravir and remdesivir molecules bind to 3-chymotrypsin like protease with energies of 6.18 and -6.52 kcal/mol in contrast to -5.62 and -3.91 kcal/mol for RNA dependent RNA polymerase. Further, hydrophobic interactions and salt bridge formations cement drug bindings with 3-chymotrypsin like protease, but not with RNA dependent RNA polymerase. Molecular dynamic simulation experiments, performed under certain experimental constraints reveal that the root mean square flexibilities of active residues in drug complexes with 3-chymotrypsin like protease are lower than in free 3-chymotrypsin like protease making the former more stable than the latter because of their rigidity and stabilities. Both drugs may hence serve as good therapeutic options for early stages of coronavirus disease 2019. However, more severe symptoms may be treated better with favipiravir due to its better binding with RNA dependent RNA polymerase, as compared to remdesivir. The "one drug does not fit all" concept is true for coronavirus disease 2019 as it is being currently realized by clinicians all around the world. Hence precise knowledge about critical interactions of these drugs with the viral enzymes will help medicos make vital therapeutic decisions on interventional options for patients who report to hospitals without over symptoms or with varying degrees of disease severity. [ABSTRACT FROM AUTHOR]

Background: Drug development strategies for treating COVID-19 focus on actives that either physically block angiotensin-converting enzyme-2 (ACE-2) receptors (viral entry point), or those, which inactivate viral proteases like 3CLpro or RdRp, inside the infected host cells. Objectives: The objective of the present study is to virtually screen phytochemicals for both these purposes. Methods: Molecular docking, molecular dynamic simulation (MDS) and multiple sequence alignment were employed. Results: All the screened phytochemical actives showed negative binding energies with their respective targets, attesting good complex stabilities. Among each set of ten actives, for blocking ACE-2 receptors and for inactivation of 3CLpro and RdRp, DichamanetinACE-2, Glabrene-3CLpro and Naringenin-RdRp complexes were most stable, with binding energies of -9.8, -9.11 and -7.7 Kcal/mol respectively. MDS studies of these representative actives and their complexes, also attested to complex stabilities. Multiple sequence alignment analysis of nine significant amino acid residues of the Homo sapiens ACE-2 receptor, with nine different species, showed conservation of several residues. Conclusion: A set of phytochemicals actives can block ACE-2 receptors and prevent the entry of SARS-CoV-2 into host endothelial cells. Two other sets of actives can inactivate viral 3CLpro and RdRp enzymes and prevent replication of SARS-CoV-2 inside host cells. They all can hence be further explored for the control of COVID-19. [ABSTRACT FROM AUTHOR]

An important consideration in software-defined networks (SDNs), is that one SDN application, through a bug or API misuse, can break an entire SDN. While previous works have tried to mitigate such concerns by implementing access control mechanisms (permission models) for an SDN controller, they commonly require serious manual efforts in creating a permission model. Moreover, they do not support flexible permission models, and they are often tightly coupled with a specific SDN controller. To address such limitations, we introduce an automated permission generation and verification system called VOGUE. A distinguishing aspect of VOGUE is that it automatically generates flexible permission models and yet is completely separated from the SDN controller implementation. To demonstrate the feasibility of our approach, we implement a prototype, evaluate its completeness and soundness, and examine its performance. In addition, to show the effectiveness of VOGUE, we demonstrate its use cases and security impact to SDN in the context of popular SDN controllers. [ABSTRACT FROM AUTHOR]

The performance and operational characteristics of the Domain Name System (DNS) protocol are of deep interest to the research and network operations community. In this paper, we present measurement results from a unique dataset containing more than 26 billion DNS query–response pairs collected from more than 600 globally distributed recursive DNS resolvers. We use this dataset to reaffirm findings in published work and notice some significant differences that could be attributed both to the evolving nature of DNS traffic and to our differing perspective. For example, we find that although characteristics of DNS traffic vary greatly across networks, the resolvers within an organization tend to exhibit similar behavior. We further find that more than 50% of DNS queries issued to root servers do not return successful answers, and that the primary cause of lookup failures at root servers is malformed queries with invalid top-level domains (TLDs). Furthermore, we propose a novel approach that detects malicious domain groups using temporal correlation in DNS queries. Our approach requires no comprehensive labeled training set, which can be difficult to build in practice. Instead, it uses a known malicious domain as anchor and identifies the set of previously unknown malicious domains that are related to the anchor domain. Experimental results illustrate the viability of this approach, i.e., we attain a true positive rate of more than 96%, and each malicious anchor domain results in a malware domain group with more than 53 previously unknown malicious domains on average. [ABSTRACT FROM AUTHOR]

Ability of the ionic liquids to alterthe structural stabilityof proteins in aqueous solution is a topic of considerable interestin modern bioscientific research because of possible applicationsof these substances in protein purification and as refolding agents.A few early studies involving the imidazolium ionic liquids have demonstratedtheir role as both denaturants and refolding agents. As the influenceof an ionic liquid on a given protein depends on the identity of bothspecies, it is necessary to extend the studies to a wider number ofionic liquids and proteins to obtain insight into the mechanism ofinteraction between the two and to arrive at a comprehensive picture.It is in this context that we have studied the effect of two morpholiniumsalts, [Mor1,2][Br] and [Mor1,4][Br], differing in the alkyl chainlength of cation, on chicken egg white lysozyme in its native andchemically denatured states employing primarily the fluorescence correlationspectroscopy (FCS) technique. Fluorescence signal of Alexa488-labeledlysozyme (A488-Lysz) has been used to determine the changes in hydrodynamicradius of protein in the presence of additives. The results reveala conformational dynamics of lysozyme with a time constant of 56 ±10 μs in its native state. It is observed, when in its nativestate, both the morpholinium salts induce structural changes of lysozyme.However, when in its unfolded state, [Mor1,4][Br] at low concentrationcompacts the protein, but at higher concentration, it stabilizes theunfolded state, unlike [Mor1,2][Br], which compacts lysozyme at bothlow and high concentrations. A comparison of the effect of these saltsand arginine, a protein stabilizer, on lysozyme indicates that [Mor1,2][Br]is a superior compacting agent for the unfolded state of the proteincompared to arginine. [ABSTRACT FROM AUTHOR]

The nature of binding of specially designed charge transfer (CT) fluorophore at the hydrophobic protein interior of human serum albumin (HSA) has been explored by massive blue-shift (82 nm) of the polarity sensitive probe emission accompanying increase in emission intensity, fluorescence anisotropy, red edge excitation shift, and average fluorescence lifetimes. Thermal unfolding of the intramolecular CT probe bound HSA produces almost opposite spectral changes. The spectral responses of the molecule reveal that it can be used as an extrinsic fluorescent reporter for similar biological systems. Circular dichrosim spectra, molecular docking, and molecular dynamics simulation studies scrutinize this binding process and stability of the protein probe complex more closely. © 2012 Wiley Periodicals, Inc. Biopolymers 97: 766-777, 2012. [ABSTRACT FROM AUTHOR]

Photoinduced intramolecular charge transfer produced a polar excited state in trans-3-(4-monomethylaminophenyl)acrylonitrile (MMAPA), rendering the resulting emission sensitive to the medium polarity. Strong binding interaction of silver nanoparticles with the probe was observed, causing fluorescence quenching through the static quenching process. The probe MMAPA was found to bind to the less polar hydrophobic, restricted proteinous environment of bovine serum albumin (BSA) resulting in the blue shift of the emission maximum with an increase in emission intensity and fluorescence anisotropy. Studies using site markers of flufenamic acid and phenylbutazone coupled with molecular docking results predicted that the binding site of the probe is in between subdomains IIIA and IB of BSA and is different from the conventional Sudlow sites. The denaturation of the probe-bound BSA by urea or heat released the probe from this proteinous environment to water marked by exactly reverse spectral changes. On the interaction of silver nanoparticles with the probe bound protein, the probe was observed to move from its binding site in the protein to the Ag0nanoparticle surface involving conformational changes of the protein near the probe binding site. [ABSTRACT FROM AUTHOR]

Changes in polarity at the immediate binding site in protein bovine serum albumin (BSA) produces distinct changes in the solvent polarity-dependent emission band of fluorescence probe E-3-(4-dimethylamino-naphthalen-1-yl)-acrylic acid. Steady-state spectroscopy and time-resolved spectroscopy have been used to investigate this binding process. Attaching the probe to BSA and then monitoring its spectral changes with increasing urea concentration and raising temperature has also tracked the denaturation of BSA chemically and thermally. The polarity of the microenvironment was investigated employing the Reichardt ET(30) scale. Fluorescence anisotropy, red edge excitation shifts and acrylamide-induced quenching of fluorescence have been exploited to gain better insight into this binding process. [ABSTRACT FROM AUTHOR]

Abstract: Photophysical properties of methyl ester of 2,6-dimethyl-1-amino-4-benzoic acid (M26DMB) have been investigated using steady state absorption and emission spectroscopy and time-resolved emission spectroscopy. Interestingly, not only in polar solvents, the molecule M26DMB having a weak primary amino donor group shows broad red-shifted emission band even in non-polar environment which in all probability arises from closely spaced local and charge transfer (CT) states. Clear dual fluorescence in polar protic solvents comprises of less intense local emission band and strong red-shifted CT band. The position of the red-shifted emission band is dependent on both the polarity and the hydrogen-bonding ability of the solvent. [Copyright &y& Elsevier]

The present work reports supramolecular interaction of [6,6]-phenyl C 71 butyric acid methyl ester (PC 70 BM) with two designed diporphyrin molecules having dithiophene ( 1 ) and carbazole ( 2 ) spacer in solvent having varying polarity. Studies on complex formation reveal relatively higher binding constant for PC 70 BM/ 2 complex in all the solvent studied. Solvent dependence of charge separation and charge recombination processes in PC 70 BM/diporphyrin non-covalent complexes has been well established in present work. Donor–acceptor geometry and stabilization of the singlet excited state of the diporphyrin during charge recombination are considered to be the possible reasons for this behavior. [ABSTRACT FROM AUTHOR]