Discovering potential stabilizers for KRAS22RT G-quadruplex DNA: an alternative next generation approach to treat pancreatic cancer.

KRAS is the signature gene responsible for the occurrence of pancreatic cancer, which is a complex, multifactorial and intractable lethal malignancy. Prevention and treatment of the ailment have always been a key motivation behind the search for new therapeutic drug molecules. G-quadruplexes are non-canonical guanine-rich secondary structures, commonly formed at eukaryotic telomeric ends, oncogenic promotors and G-rich regions of the DNA. These G-quadruplexes play a crucial role in the regulation of gene expression and maintenance of genome integrity, therefore, they are considered as emerging potential therapeutic drug targets. The present study is concerned with the discovery of a potential stabilizer for KRAS22RT G-quadruplex DNA, located in the NHE region of the promotor, while inhibiting the upregulation of KRAS proto-oncogene, as an alternative approach for the treatment of pancreatic cancer. Various chemical libraries have been virtually screened against the targeted G4 structure and 143 compounds showed promising results. However, molecular dynamic studies, ADME and toxicity analyses predicted that three compounds belonging to the class of tetra-substituted phenanthrolines (i.e., 7i, 7j and 7k) can not only effectively stabilize KRAS22RT G4 structure but also have least toxic effects in the in vivo system. Therefore, it is highly recommended to further investigate their effectiveness and efficacy through experimental analysis in laboratory.Communicated by Ramaswamy H. Sarma.

Virtual screening and molecular dynamics simulation analysis of Forsythoside A as a plant-derived inhibitor of SARS-CoV-2 3CLpro.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a more severe strain of coronavirus (CoV) that was first emerged in China in 2019. Available antiviral drugs could be repurposed and natural compounds with antiviral activity could be safer and cheaper source of medicine for SARS-CoV-2. 78 natural antiviral compounds database was identified from literature and virtual screening technique was applied to identify potential 3-chymotrypsin-like protease (3CLpro) inhibitors. Molecular docking studies were conducted to analyze the main protease (3CLpro) and inhibitors interactions with key residues of active site of target protein (PDB ID: 6LU7), active site constitute the part of active domain I and II of 3CLpro. 10 compounds with highest dock score were subjected to calculate ADMET parameters to figure out drug-likeness. Molecular dynamic (MD) simulation of the selected lead was performed by Amber simulation package to understand the conformational changes in docked complex. MD simulations analysis (RMSD, RMSF, Rg, BF, HBs, and SASA plots) of lead bounded with 3CLpro, hence revealed the important structural turns and twists during MD simulations from 0 to 100 ns. MM-PBSA/GBSA methods has also been applied for the estimation binding free energy (BFE) of the selected lead-complex. The present study has identified lead compound "Forsythoside A" an active extract of Forsythia suspense as SARS-CoV-2 3CLpro inhibitor that can block the viral replication and translation. Structural analysis of target protein and lead compound performed in this study could contribute to the development of potential drug against SARS-CoV-2 infection.

Prevalence of Psychosocial and Behavioral Aspects in Victims of Motorcycle Accidents in Civil Hospital, Karachi.

Introduction Motorcycles are common in a developing nation like Pakistan. In addition to their benefits, motorcycles carry a high risk for accident and injury. Many factors can exacerbate the risk of motorcycle operation including the use of mobile phones while riding, a lack of knowledge of traffic rules, not following road rules or non-satisfactory vehicle health and road conditions. Along with these physical factors, some psychosocial aspects also impact risks, including aggressive behavior of drivers or variations in driving patterns associated with changes in driver mood. Objective We conducted this study to determine the association of rider/operator behavioral and psychosocial factors with motor vehicle crashes. Methods We conducted a cross-sectional study on the patients of Civil Hospital in Karachi, Pakistan aged between 15 to 65 years. Data were collected from 150 patients in the outpatient department and emergency room via a questionnaire assessing driver biodata, license details, socioeconomic status, and their behavioral and psychosocial conditions. Inclusion criteria were limited to patients with motorcycle accidents only; patients involved in accidents from any other form of vehicle were excluded. Result Of the 150 patients, 70% were reported varying their driving speed with fluctuating moods, 80% rode aggressively when they have any social or financial issue, and 57% became annoyed with another driver's behavior-all of which highlight the influence of psychosocial factors in motorcycle crashes. Concerning behavioral factors, 88% of drivers were involved in unofficial races, 44% reported overtaking slower drivers, and 80% violated traffic signals on a regular basis. These results suggest that behavioral and psychosocial factors have a major influence on the victims of motorcycle accidents and are an important cause of injury due to crashes. Conclusion Psychosocial and behavior aspects play a critical role in motorcycle accidents. Riders experiencing family-related or social-related stress and those with an aggressive personality are more prone to have a motorcycle accident than riders who do not have those stressors. Additional measures should be taken to raise awareness regarding these important contributing factors, including stress management in driving education.