The pandemic COVID‐19 has become a global panic‐forcing life towards a compromised “new normal.” Antiviral therapy against SARS‐CoV‐2 is still lacking. Thus, development of natural inhibitors as a prophylactic measure is an attractive strategy. In this context, this work explored phytochemicals as potential inhibitors for SARS‐CoV‐2 by performing all atom molecular dynamics simulations using high performance computing for 8 rationally screened phytochemicals from Withania somnifera and Azadirachta indica and two repurposed drugs docked with the spike glycoprotein and the main protease of SARS‐CoV‐2. These phytochemicals were rationally screened from 55 Indian medicinal plants in our previous work. MM/PBSA, principal component analysis (PCA), dynamic cross correlation matrix (DCCM) plots and biological pathway enrichment analysis were performed to reveal the therapeutic efficacy of these phytochemicals. The results revealed that Withanolide R (−141.96 KJ/mol) and 2,3‐Dihydrowithaferin A (−87.60 KJ/mol) were with the lowest relative free energy of binding for main protease and the spike proteins respectively. It was also observed that the phytochemicals exhibit a remarkable multipotency with the ability to modulate various human biological pathways especially pathways in cancer. Conclusively we suggest that these compounds need further detailed in vivo experimental evaluation and clinical validation to implement them as potent therapeutic agents for combating SARS‐CoV‐2.
Research on extremostable proteins has seen immense growth in the past decade owing to their industrial importance. Basic research of attributes related to extreme-stability requires further exploration. Modern mechanistic approaches to engineer such proteins in vitro will have more impact in industrial biotechnology economy. Developing a priori knowledge about the mechanism behind extreme-stability will nurture better understanding of pathways leading to protein molecular evolution and folding. This review is a vivid compilation about all classes of extremostable proteins and the attributes that lead to myriad of adaptations divulged after an extensive study of 6495 articles belonging to extremostable proteins. Along with detailing on the rationale behind extreme-stability of proteins, emphasis has been put on modern approaches that have been utilized to render proteins extremostable by protein engineering. It was understood that each protein shows different approaches to extreme-stability governed by minute differences in their biophysical properties and the milieu in which they exist. Any general rule has not yet been drawn regarding adaptive mechanisms in extreme environments. This review was further instrumental to understand the drawback of the available 14 stabilizing mutation prediction algorithms. Thus, this review lays the foundation to further explore the biophysical pleiotropy of extreme-stable proteins to deduce a global prediction model for predicting the effect of mutations on protein stability.
Organic solvent-stable lipases have pronounced impact on industrial economy as they are involved in synthesis by esterification, interesterification, and transesterification. However, very few of such natural lipases have been isolated till date. A study of the recent past provided few pillars to rely on for this work. The three-dimensional structure, inclusive of the surface and active site, of 29 organic solvent-stable lipases was analyzed by subfamily classification and protein solvent molecular docking based on fast Fourier transform correlation approach. The observations revealed that organic solvent stability of lipases is their intrinsic property and unique with respect to each lipase. In this paper, factors like surface distribution of charged, hydrophobic, and neutral residues, interaction of solvents with catalytically immutable residues, and residues interacting with essential water molecules required for lipase activity, synergistically and by mutualism contribute to render a stable lipase organic solvent. The propensity of surface charge in relation to stability in organic solvents by establishing repulsive forces to exclude solvent molecules from interacting with the surface and prohibiting the same from gaining entry to the protein core, thus stabilizing the active conformation, is a new finding. It was also interesting to note that lipases having equivalent surface-exposed positive and negative residues were stable in a wide range of organic solvents, irrespective of their LogP values.
The COVID-19 pandemic resulted in millions of people being quarantined, impacting the world economy and health sector. There is no existing proven treatment for this disease. It may takea long time until a good candidate vaccine or a potent drug is made available in the market. Therefore, there is a need to search for alternative therapy. In the context, this work explored natural compounds from Indian medicinal plants to develop a prophylactic treatment regimen that will be instrumentalin controlling the spread of the deadly virus. In this work 1916 phytochemicals from 55 Indian medicinal plants, reported to possess anti-viral properties, were subjected to virtual screening on 8 structural and non-structural SARS-CoV-2 protein targets. Docking interactions, ADME and toxicity profiles of the 66 screened phytochemicals were correlated with 21 repurposed drugs that have been most cited in literature to be effective against SARS-CoV-2. Steroidal lactones from Withaniasomnifera and triterpenoids from Azadirachtaindica- with docking score ranging from -13 kcal/mol upto -6 kcal/mol were identified to occupy the top scoring virtually screened phytochemicals against the various targets of SARS-CoV-2. Importantly this work proposes that a concoction of these phytochemicals can act as prophylactic anti-viral medicine to control the spread of SARS-CoV-2 and also enhance natural immunity as the first line of defence towards such a deadly virus.
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