Key Points Question Were there changes in the rate and characteristics of deaths from drug overdose before vs during the COVID-19 pandemic in Rhode Island? Findings In this population-based cohort study of 470 adults who died of drug overdose in Rhode Island from January 1 to August 31 in 2019 and 2020, rates of death from overdose among men, deaths involving synthetic opioids, and deaths occurring in personal residences increased significantly in 2020 compared with 2019. Deaths due to overdose also increased among people experiencing job loss and in subgroups with mental health diagnoses. Meaning These findings suggest that policy and service delivery interventions that are responsive to emerging characteristics of deaths from drug overdose are needed to curtail these deaths.

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Background NOX-1 overexpression has been observed in various studies, persons with diabetes or cardiovascular conditions. NOX-1 orchestrates the disease pathogenesis of various cardiovascular conditions such as atherosclerotic plaque development and is a very crucial biomarker. Therefore, this study was carried out to deduce the three-dimensional modelled structure of NOX-1 using DeepMind AlphaFold-2 to find meaningful insight into the structural biology. Extensive in silico approaches have been used to determine the active pocket, virtually screen large chemical space to identify potential inhibitors. The role of the key amino acid residues was also deduced using alanine scanning mutagenesis contributing to the catalytic process and to the overall stability of NOX-1. Results The modelled structure of NOX-1 protein was validated using ERRAT. The ERRAT statistics with 9 amino acids sliding window have shown a confidence score of 96.937%. According to the Ramachandran statistics, 96.60% of the residues lie within the most favoured region, and 2.80% of residues lie in the additionally allowed region, which gives an overall of 99.4% residues in the three quadrants in the plot. GKT-831 which is a referral drug in this study has shown a GOLD interaction score of 62.12 with respect to the lead molecule zinc000059139266 which has shown a higher GOLD score of 78.07. Alanine scanning mutagenesis studies has shown that Phe201, Leu98 and Leu76 are found to be the key interacting residues in hydrophobic interactions. Similarly, Tyr324, Arg287 and Cys73 are major amino acid residues in the hydrogen bond interactions. Conclusions NOX-1 overexpression leads to heightened ROS production resulting in catastrophic outcomes. The modelled structure of NOX-1 has a good stereochemistry with respect to Ramachandran plot. The lead molecule zinc000059139266 has shown to have a very high interaction score of 78.07 compared to the referral drug GKT-831 with a score of 62.12. There is an excellent scope for the lead molecule to progress further into in vitro and in vivo studies.

The mutations present in the spike protein of omicron, a new variant of SARS CoV2 favours the high transmission of Covid in fection. To control the rate of infection finding an effective alternative drug can be beneficial. In our work, we have repurposed 1930 FDA approved drugs in which best top five lead compounds based on their GOLD score are Telotris tetethyl, Oxyglutatione, Pentamidinium, Clindamycin palmitate, Pentagastrin having GOLD score 53.2481, 52.7613, 52.7513, 52.5499, 52.5473. These compounds were selected for further molecular interactions & visualization studies with the spike region of omicron. The homology modelling of the spike protein with 30 induced mutations were carried out and the quality of the modelled structure was found to be reasonably good with 80% of its residue falling in the accepted region of Ramachandran plot. The frustration analysis of the protein and ligand complexes were analysed to find the contribution of residues in overall functioning of the protein.

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