Structure based virtual screening and molecular simulation study of FDA-approved drugs to inhibit human HDAC6 and VISTA as dual cancer immunotherapy.

Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them, V-domain immunoglobulin suppressor of T cell activation (VISTA) has been explored as a promising therapeutic target. Besides, histone deacetylase 6 (HDAC6) has been demonstrated to be efficacious target for several cancers. The current theoretical work was performed to explore the virtual repurposing of the FDA-approved drugs as inhibitors against these two (VISTA and HDAC6) cancers therapeutic targets. The crystal structure of the two proteins were downloaded from PDB and subjected to virtual screening by DrugRep webserver while using FDA-approved drugs library as ligands database. Our study revealed that Oxymorphone and Bexarotene are the top-ranked inhibitors of VISTA and HDAC6, respectively. The docking score of Bexarotene was predicted as - 10 kcal/mol while the docking score of Oxymorphone was predicted as - 6.2 kcal/mol. Furthermore, a total of 100 ns MD simulation revealed that the two drugs Oxymorphone and Bexarotene formed stable complexes with VISTA and HDAC6 drug targets. As compared to the standard drug the two drugs Oxymorphone and Bexarotene revealed great stability during the whole 100 ns MD simulation. The binding free energy calculation further supported the Root Mean Square Deviation (RMSD) result which stated that as compared to the ref/HDAC6 (- 18.0253 ± 2.6218) the binding free energy score of the Bexarotene/HDAC6 was good (- 51.9698 ± 3.1572 kcal/mol). The binding free energy score of Oxymorphone/VISTA and Ref/VISTA were calculated as - 36.8323 ± 3.4565, and - 21.5611 ± 4.8581 respectively. In conclusion, the two drugs deserve further consideration as cancer treatment option.

Epidemiological Trends of Acute Chemical Poisoning among Children over a Recent Three-Year Period in Saudi Arabia.

Acute intoxication from chemicals is a major medical emergency that can result in illness and mortality. This retrospective study aims to evaluate acute chemical poisoning incidents among children in Saudi Arabia from 2019 to 2021. A total of 3009 children were recorded as being chemically intoxicated. The SPSS/PC statistics package was used for the statistical analysis. The acute chemical poisoning incidents that occurred in the age groups were <1 year: 237 (7.8%), 1-5 years: 2301 (76.4%), 6-12 years: 214 (7.1%), and 13-19 years: 257 (8.5%). The mean rate of acute chemical poisoning in the northern region was 40.1%. The most common poisonous agents were organic solvents (20.4%) and disinfection agents (22.7%). Interestingly, there is a significant relationship between the different types of acute chemical poisoning and various factors, including gender, age, the location where acute chemical intoxication occurred, the type of exposure, and whether these were intentional or unintentional events. The data suggest that the northern region of Saudi Arabia has had the highest number of recorded incidents of acute chemical poisoning over the last three years (2019-2021). Individuals between 1-5 years old were the worst hit. Organic solvents and detergents were to blame for the acute unintentional chemical poisonings that took place in homes. Therefore, educating the public about chemical poisoning and reducing children's exposure to toxic chemicals requires educational programs, which may help to reduce chemical poisoning occurrence.