In Silico Screening of Chlorogenic Acids from Plant Sources against Human Translocase-I to Identify Competitive Inhibitors to Treat Diabetes.

Chlorogenic acids (CHLs) are known to competitively bind to translocase-I (T1) of the glucose-6-phosphatase (G6 Pase) system, thereby inhibiting the transport of glucose-6-phosphate (G6P). This competitive binding results in a consequential reduction in blood sugar levels. In this study, steered molecular dynamics (SMD) simulation is employed to investigate the interaction between T1 and G6P, aiming to gain insights into the binding dynamics and diffusion process of G6P through T1. A database comprising 41 CHLs sourced from various plants was developed, subjected to minimization, and screened against T1 through conventional docking methods. The docked conformations were fed into a newly developed customized scoring method incorporating contact-based weights to assess the binding affinities that systematically rank and identify the most effective competitive inhibitors. Among the screened CHLs, 1-methoxy 3,5-dicaffeoylquinic acid, 3,4 dicaffeoyl quinic acid, and 3,4,5-tricaffeoylquinic acid stood out as the top three inhibitors, showcasing crucial atomic interactions with key residues within the binding pocket of T1, and these CHLs are sourced from readily available plants, diminishing reliance on coffee as the predominant CHL source. Along with the devised scoring function, which serves as a valuable tool for virtual screening and lead optimization in drug development, this study also marks a pioneering effort as it involves the modeling of the human translocase and unravels the mechanism of binding and diffusion of G6P within human T1, providing valuable insights into the structural prerequisites for successfully inhibiting the G6P system, laying the foundation for a rational approach to drug design. This research contributes to the progress of drug discovery strategies focused on the G6P system, presenting potential therapeutic avenues for addressing metabolic disorders linked to an impaired glucose metabolism.

Whole lung irradiation as a novel treatment for COVID-19: Final results of the prospective randomized trial (WINCOVID trial).

BACKGROUND AND PURPOSE: The ability of low dose radiotherapy (LDRT) to control the unprecedented cytokine release associated with COVID-19 pathogenesis has been an area of widespread research since the COVID pandemic. It has not been studied adequately whether the anti-inflammatory effect of LDRT provides additional benefit when used concurrently with steroids amongst other standard pharmacologic therapy. MATERIAL AND METHODS: 51 RT-PCR positive COVID-19 patients were recruited between November 2020 and July 2021. 34 patients were allotted to receive 0.5 Gy single session LDRT along with standard pharmacologic therapy while 17 patients received standard pharmacologic therapy alone. All had SpO2 <94% on room air, respiratory frequency >24/min and SpO2/FiO2 (SF) ratio between >89 but <357. All patients underwent a baseline CT scan. They were followed up for 28 days during when serial SF ratio, blood biomarkers (CRP, Serum ferritin, IL-6), Absolute lymphocyte count (ALC), repeat CT scan were performed at pre-defined time points. RESULTS: LDRT showed a statistically significant early improvement in oxygenation, an early time to clinical recovery, early hospital discharge and better radiological resolution compared to control group. There was no statistically significant difference between the two groups with respect to ALC or blood biomarkers at any of the measured time points. The 28-day mortality rate did not show statistically significant difference between the two groups. CONCLUSION: LDRT can be considered for selected oxygen-dependent moderate to severe COVID-19 patients for rapid relief of respiratory distress. It can be safely combined with standard pharmacologic treatment in such patients for added clinical benefit.