Identification of a 1, 8-naphthyridine-containing compound endowed with the inhibition of p53-MDM2/X interaction signaling: a computational perspective.

Various studies have established that molecules specific for MDMX inhibition or optimized for dual inhibition of p53-MDM2/MDMX interaction signaling are more suitable for activating the Tp53 gene in tumor cells. Nevertheless, there are sparse numbers of approved molecules to treat the health consequences brought by the lost p53 functions in tumor cells. Consequently, this study explored the potential of a small molecule ligand containing 1, 8-naphthyridine scaffold to act as a dual inhibitor of p53-MDM2/X interactions using computational methods. The results obtained from quantum mechanical calculations revealed our studied compound entitled CPO is more stable but less reactive compared to standard dual inhibitor RO2443. Like RO2443, CPO also exhibited good non-linear optical properties. The results of molecular docking studies predicted that CPO has a higher potential to inhibit MDM2/MDMX than RO2443. Furthermore, CPO was stable over 50 ns molecular dynamics (MD) simulation in complex with MDM2 and MDMX respectively. On the whole, CPO also exhibited good drug-likeness and pharmacokinetics properties compared to RO2443 and was found with more anti-cancer activity than RO2443 in bioactivity prediction. CPO is anticipated to elevate effectiveness and alleviate drug resistance in cancer therapy. Ultimately, our results provide an insight into the mechanism that underlay the inhibition of p53-MDM2/X interactions by a molecule containing 1, 8-naphthyridine scaffold in its molecular structure.

Understanding the genetic determinant of severity in viral diseases: a case of SARS-Cov-2 infection.

Background: Numerous research studies have identified specific human gene variants that affect enhanced susceptibility to viral infections. More recently is the current pandemic where the SARS-CoV-2 infection has shown a high degree of person-to-person clinical variability. A wide range of disease severity occurs in the patients' experiences, from asymptomatic cases, mild infections to serious life threatening conditions requiring admission into the intensive care unit (ICU). Main body of the abstract: Although, it is generally reported that age and co-morbidities contribute significantly to the variations in the clinical outcome of the scourge of COVID-19, a hypothetical question of the possibility of genetic involvement in the susceptibility and severity of the disease arose when some unique severe outcomes were seen among young patients with no co-morbidity. The role human genetics play in clinical response to the viral infections is scarcely understood; however, several ongoing researches all around the world are currently focusing on possible genetic factors. This review reports the possible genetic factors that have been widely studied in defining the severity of viral infections using SARS-CoV-2 as a case study. These involve the possible involvements of ACE2, HLA, and TLR genes such as TLR7 and TLR3 in the presentation of a more severe condition. Short conclusion: Understanding these variations could help to inform efforts to identify people at increased risk of infection outbreaks through genetic diagnosis of infections by locating disease genes or mutations that predispose patients to severe infection. This will also suggest specific targets for therapy and prophylaxis.