SARS-CoV-2 omicron spike simulations: broad antibody escape, weakened ACE2 binding, and modest furin cleavage.

The recent emergence of the omicron variant of the SARS-CoV-2 virus with large numbers of mutations has raised concern about a potential new surge in infections. Here we use molecular dynamics to study the biophysics of the interface of the BA1 and BA2 omicron spike protein binding to (i) the ACE2 receptor protein, (ii) antibodies from all known binding regions, and (iii) the furin binding domain. Our simulations suggest that while there is a significant reduction of antibody (Ab) binding strength corresponding to escape, the omicron spikes pay a cost in terms of weaker receptor binding as measured by interfacial hydrogen bonds (H-bond). The furin cleavage domain (FCD) is the same or weaker binding than the delta variant, suggesting lower fusogenicity resulting in less viral load and disease intensity than the delta variant. IMPORTANCE The BA1 and BA2 and closely related BA2.12.2 and BA.5 omicron variants of SARS-CoV-2 dominate the current global infection landscape. Given the high number of mutations, particularly those which will lead to antibody escape, it is important to establish accurate methods that can guide developing health policy responses that identify at a fundamental level whether omicron and its variants are more threatening than its predecessors, especially delta. The importance of our work is to demonstrate that simple in silico simulations can predict biochemical binding details of the omicron spike protein that have epidemiological consequences, especially for binding to the cells and for fusing the viral membrane with the cells. In each case, we predicted weaker binding of the omicron spike, which agreed with subsequent experimental results. Future virology experiments will be needed to test these predictions further.

Insight into structural features of phenyltetrazole derivatives as ABCG2 inhibitors for the treatment of multidrug resistance in cancer.

ABCG2 is the principal ABC transporter involved in the multidrug resistance of breast cancer. Looking at the current demand in the development of ABCG2 inhibitors for the treatment of multidrug-resistant cancer, we have explored structural requirements of phenyltetrazole derivatives for ABCG2 inhibition by combining classical QSAR, Bayesian classification modelling and molecular docking studies. For classical QSAR, structural descriptors were calculated from the free software tool PaDEL-descriptor. Stepwise multiple linear regression (SMLR) was used for model generation. A statistically significant model was generated and validated with different parameters (For training set: r = 0.825; Q2 = 0.570 and for test set: r = 0.894, r2pred = 0.783). The predicted model was found to satisfy the Golbraikh and Trospha criteria for model acceptability. Bayesian classification modelling was also performed (ROC scores were 0.722 and 0.767 for the training and test sets, respectively). Finally, the binding interactions of phenyltetrazole type inhibitor with the ABCG2 receptor were mapped with the help of molecular docking study. The result of the docking analysis is aligned with the classical QSAR and Bayesian classification studies. The combined modelling study will guide the medicinal chemists to act faster in the drug discovery of ABCG2 inhibitors for the management of resistant breast cancer.

Permcath - A Vascular Access for Hemodialysis, Our Experience in Last Two Years.

Background The double lumen tunneled catheter (Permcath) is mostly used as an alternative access, not as a temporary access in End Stage Renal Disease patients requiring hemodialysis. If there is no possibility of other access modalities, failed or unable to create native arteriovenous fistula (AVF), Permcath can be a very good alternative. Objective To find the indications, complications and results of Permcath insertion. Method We reviewed the results of 92 Permcath inserted under ultrasound guidance in two different hospitals, 45 in Sahid Dharma Bhakta National Transplant Center (SDNTC), Bhaktapur and 47 in Nidan Hospital Pvt. Ltd., Lalitpur from April 2016 to April 2018 retrospectively. Result We had inserted 55 Permcath (59.78%) in right internal jugular vein (IJV), 25 (27.17%) in left internal jugular vein and 12(13.04%) in femoral vein. In terms of major complications, two (2.17%) patients had profound hypotension, bradycardia and cardiac arrest due to left internal jugular vein tear. Three patients (3.26%) died within a week due to septicemia and 23 patients (25%) died with multiple causes within one year. Of the cases, till now in 39 cases (42.39%) Permcath has been removed. Major reasons of removal of Permcath are post renal transplant in 18 cases (19.57%), Arterio Venous Fistula maturation in 13 cases (14.13%), Infection in six patients (6.52%) and non functioning Permcath in two patients (2.17%). Conclusion Permcath remains a reliable method for short term vascular access, hence can be used as a bridge to renal transplant or arteriovenous fistula maturation.