Computational investigation of binding of chloroquinone and hydroxychloroquinone against PLPro of SARS-CoV-2.

Novel coronavirus SARS-CoV-2 has infected 18 million people with 700,000+ mortalities worldwide and this deadly numeric figure is rapidly rising. With very few success stories, the therapeutic targeting of this epidemic has been mainly attributed to main protease (Mpro), whilst Papain-like proteases (PLpro) also plays a vital role in the processing of replicase polyprotein. Multifunctional roles of PLpro such as viral polypeptide cleavage, de-ISGlyation and immune suppression have made it a promising drug target for therapeutic interventions. Whilst there have been a number of studies and others are on-going on repurposing and new-small molecule screening, albeit previously FDA approved drugs viz. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have only been found effective against this pandemic. Inspired by this fact, we have carried out molecular docking and dynamics simulation studies of FDA approved CQ and HCQ against SARS-CoV-2 PLpro. The end aim is to characterise the binding mode of CQ and HCQ and identify the key amino acid residues involved in the mechanism of action. Further, molecular dynamics simulations (MDS) were carried out with the docked complex to search for the conformational space and for understanding the integrity of binding mode. We showed that the CQ and HCQ can bind with better binding affinity with PLpro as compared to reference known PLpro inhibitor. Based on the presented findings, it can be anticipated that the SARS-CoV-2 PLpro may act as molecular target of CQ and HCQ, and can be projected for further exploration to design potent inhibitors of SARS-CoV-2 PLpro in the near future.

Environmental management partner selection for reverse supply chain collaboration: A sustainable approach.

The Indian electronics industry is facing immense pressure to include sustainability practices in order to meet customer expectations, comply with legislation and create an edge over competitors. This growing need for inclusion of sustainability is driving original equipment manufacturers (OEMs) to collaborate with third-party reverse logistics providers (3PRLPs) to sustainably manage returns. Collaboration with 3PRLP will put OEMs in a stronger position regarding compliance with government legislation, improving upon their corporate image and customer satisfaction. It is a win-win situation for the OEM. On the other hand, from the 3PRLP's point of view, it is important to know the capabilities of the OEMs before entering into a collaborative endeavour. Hence, it is firstly necessary to identify the most appropriate attributes of the manufacturer which are essential for a sustainable collaboration. In this context, the study proposes a novel framework for investigating the performance attributes of the OEMs from the economic, environmental and social aspects of sustainability. Since the evaluation of each attribute for each dimension of sustainability differs in terms of the nature of the information needed and the time and resources required, it is necessary to conduct a pre-evaluation of the attributes using the Complex Proportional Assessment (COPRAS) method. Furthermore, the shortlisted attributes for each sustainability dimension are evaluated and prioritized using the best worst method (BWM). The novelty of the attribute selection process lies in simultaneously considering the degree of importance of the attribute as well as the degree of difficulty of the collection of data required for the assessment of the OEM. The result of this study helps decision-makers and practitioners to comprehend the most influential attributes of OEMs which are crucial for collaboration, thus enhancing the overall sustainability impact of the supply chain. The managerial implications drawn from the resulting analysis provide the 3PRLP with a sustainable evaluation framework which can be ideally used for the selection of collaborative partners. The above model is validated using the case of an Indian 3PRLP company that handles electronic products.

Synthesis and docking studies of pyrazine-thiazolidinone hybrid scaffold targeting dormant tuberculosis.

The persistence of Mycobacterium tuberculosis (MTB) in dormant stage assists the pathogen to develop resistance against current antimycobactrial drugs. To address this issue, we report herein the synthesis of N-(4-oxo-2 substituted thiazolidin-3 yl) pyrazine-2-carbohydrazide derivatives designed by following the molecular hybridization approach using pyrazine and thiazolidenone scaffolds. The compounds were evaluated against MTB H37Ra and Mycobacterium bovis BCG in dormancy model. Most of the compounds had IC50 values in 0.3-1 µg/ml range. The active compounds were further tested for anti-proliferative activity against THP-1, Panc-1, A549, and MCF-7 cell lines using MTT assay and exhibited no significant cytotoxicity. We also report molecular docking studies using active analogs and MTB - Decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1) to rationalize the biological activity and to provide an insight into the probable mechanism of action and binding mode of hybridized structures. The results obtained validate the use of molecular hybridization approach and also suggest that reported compounds can provide a novel pharmacophore to synthesize lead compounds against dormat MTB.

Efficiently functionalized oxacalix[4]arenes: Synthesis, characterization and exploration of their biological profile as novel HDAC inhibitors.

A series of novel substituted oxacalix[4]arene has been synthesized and explored for their biological profile by evaluating anticancer, antifungal and antibacterial properties. The derivatives have been characterized by various spectroscopic techniques such as IR, (1)H NMR, (13)C NMR and Mass spectrometry. Many compounds showed strong inhibition (MIC) in the range of ∼0-50 µM with interesting cytotoxic activities against Hela cells in particular. The compounds were theoretically evaluated by docking studies as potential histone deacetylase inhibitors (HDACi). The study indicates that compounds bound adequately with HDAC, and hence complemented the experimental findings.

Many-photon dynamics of photobleaching.

A detailed dynamical theory of photobleaching by periodical sequences of laser pulses is presented. The theory is used for interpretation of recent experiments with pyrylium salts. Our simulations are based on first-principles simulations of photoabsorption cross-sections and on empirical rate constants. Two competitive channels of photobleaching, namely, photobleaching from the lowest excited singlet and triplet states and from higher excited states, are found to explain different intensity dependences of the photobleaching rates in different samples. The process includes two-photon excitation from the ground state to the first or second excited singlet states and one-photon excitation from the first singlet or triplet states to higher excited states. The fluorescence follows double-exponential dynamics with two characteristic times. The first and the shorter one is the equilibrium settling time between the ground and the lowest triplet states. The second characteristic time, the time of photobleaching, is responsible for the long-term dynamics. The effective rate of photobleaching from the first excited singlet and lowest triplet states depends differently on the irradiance in comparison with the photobleaching in higher states. The first channel is characterized by a quadratic intensity dependence in contrast to the second channel that shows a cubic dependence. The competition between these photobleaching channels is very sensitive to the rate constants as well as to the repetition rate, the pulse duration, and the peak intensity. The double-exponential decay of the fluorescence is explained by the spatial inhomogeneity of the light beam. The findings in this work are discussed in terms of the possibility of using many-photon-induced photobleaching for new three-dimensional read-write devices.

An incidental case of breast cysticercosis associated with fibroadenoma.

It is unusual for cysticercosis to occur in the substance of the breast. Only a few cases have been described in the literature. We report a case of cysticercosis perched on fibroadenoma of breast found on surgical excision in a 35 year old Nepali woman. The patient had no discernible evidence of cysticercosis in the other organs.