Evaluation of action of steroid molecules on SARS-CoV-2 by inhibiting NSP-15, an endoribonuclease.

Many countries in the world have recently experienced an outbreak of COVID-19, turned out to be a pandemic which significantly affected the world economy. Among many attempts to treat/control infection or to modulate host immunity, many small molecules including steroids were prescribed based on their use against other viral infection or inflammatory conditions. A recent report established the possibility of usage of a corticosteroid against the virus through inhibiting NSP-15; an mRNA endonuclease of SARS-CoV-2 and thereby viral replication. This study aimed to identify potential anti-viral agents for the virus through computational approaches and to validate binding properties with the protein target through molecular dynamics simulation. Unlike the conventional approaches, dedicated data base of steroid like compounds was used for initial screening along with dexamethasone and cortisone, which are used in the treatment of COVID-19 affected population in some countries. Molecular docking was performed for three compounds filtered from data base in addition to dexamethasone and Cortisone followed by molecular dynamics simulation analysis to validate the dynamics of binding at the active site. In addition, analysis of ADME properties established that these compounds have favorable drug-like properties. Based on docking, molecular dynamics simulation studies and various other trajectory analyses, compounds that are identified could be suggested as therapeutics or precursors towards designing new anti-viral agents against SARS-CoV-2, to combat COVID-19. Also, this is an attempt to study the impact of steroid compounds on NSP-15 of SARS-CoV-2, since many steroid like compounds are used during the treatment of COVID-19 patients.

Insights in the structural understanding of amyloidogenicity and mutation-led conformational dynamics of amyloid beta (Aß) through molecular dynamics simulations and principal component analysis.

Abnormal protein aggregation in the nervous tissue leads to several neurodegenerative disorders like Alzheimer's disease (AD). In AD, accumulation of the amyloid beta (Aß) peptide is proposed to be an early important event in pathogenesis. Significant research efforts are devoted so as to understand the Aß misfolding and aggregation. Molecular dynamics (MD) simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-ß in relation to the pathologies of AD. Present work describes the MD simulations for 100 ns so as to probe the structural and conformational dynamics of Aß1-42 assemblies and its mutants. Essential dynamics analysis with respect to conformational deviation of Cα was evaluated to identify the largest residual fluctuation of Cα. Conformational stability of all Aß mutants was analyzed by computing RMSD, deciphering the convergence is reached in the last 20 ns in all replicas. To highlight the low frequency mode of motion corresponding to the highest amplitude, atomic displacements seen in trajectory, distance pair principal component analysis (dpPCA) was performed, which adumbrated mutations strongly affect the conformational dynamics of investigated model when compared with wild type. Dynamic cross correlation matrix (DCCM) also suggests the conserved interactions of wild Aß and imply mutations in ß3-ß4 loop region induce deformity and residual fluctuations as observed from simulation. Present study indicate the mutational energy landscape which induces deformation leading to fibrillation.Communicated by Ramaswamy H. Sarma.

BODIPY based realtime, reversible and targeted fluorescent probes for biothiol imaging in living cells.

Real-time live cell imaging and quantification of biothiol dynamics are important for understanding pathophysiological processes. However, the design and synthesis of rational probes that have reversible and real-time capabilities is still challenging. In this work, we have prepared boron-dipyrrolemethene (BODIPY) based fluorescent molecules as ratiometric probes that allow the real-time biothiol dynamics to be observed in living cells. The Michael reaction between α-formyl-BODIPY (BOD-JQ) and GSH exhibited a reversible fluorogenic mechanism with fluorescent emission shifting from 592 nm to 544 nm with t1/2 = 16 ms. In particular, we showed that the probes with targeting agents are capable of detecting biothiols in mitochondria and the endoplasmic reticulum (ER) with high temporal resolution.