In-silico investigation of RPS6KB1 associated cancer inhibitor: a drug repurposing study.

The ribosomal protein S6 kinase beta-1 (RPS6KB1), also known as p70S6 kinase, plays a crucial role in various disease-related conditions such as diabetes, obesity, and cancer. Its activity is regulated by phosphorylation events, including phosphorylation of Threonine 389 in the hydrophobic motif by the mammalian target of rapamycin complex 1 (mTORC1) and phosphorylation of Threonine 229 in the activation loop by PDK1 (phosphoinositide-dependent kinase 1). However, other phenomena connected to RPS6KB1 remain unknown. In this study, we employed virtual screening and molecular docking techniques on the molecules in the ZINC library to identify potential inhibitors. Molecular dynamics (MD) simulations and MMGBSA calculations were carried out on promising compounds to determine their binding affinity and stability. We also evaluated the drug-likeness properties of the selected compounds. A comparative study between the native RPS6KB1 structure, co-crystal ligands, and the shortlisted molecules from the ZINC dataset was carried out. The identified molecules possess significant potential for future in vitro and in vivo studies, paving the way for developing effective cancer treatments.Communicated by Ramaswamy H. Sarma.

Identification of PARP12 Inhibitors By Virtual Screening and Molecular Dynamics Simulations.

Poly [adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that performs several fundamental cellular processes. Aberrant activity (mutation) in PARP12 has been linked to various diseases including inflammation, cardiovascular disease, and cancer. Herein, a large library of compounds (ZINC-FDA database) has been screened virtually to identify potential PARP12 inhibitor(s). The best compounds were selected on the basis of binding affinity scores and poses. Molecular dynamics (MD) simulation and binding free energy calculation (MMGBSA) were carried out to delineate the stability and dynamics of the resulting complexes. To this end, root means deviations, relative fluctuation, atomic gyration, compactness, covariance, residue-residue contact map, and free energy landscapes were studied. These studies have revealed that compounds ZINC03830332, ZINC03830554, and ZINC03831186 are promising agents against mutated PARP12.

Genetic Polymorphism in TNF-α-308 G/A and TNF-ß +252 A/G, as Prognostic Biomarker in Breast Cancer Patients among Indian Population.

BACKGROUND: Cytokines are the key regulator molecules that modulate immune response. Tumor necrosis factor (TNF- α-308 G/A and TNF-ß +252 A/G ) are inflammatory cytokine that control the progression of several types of cancer. They play a vital role in both tumor progression and destruction based on their concentrations. The role of TNF-α-308 G/A and TNF-ß +252 A/G gene polymorphism in the etiology of breast cancer (BC) is not clearly understood. Therefore, present study investigates the association of TNF-α -308 G/A and TNF-ß +252 A/G and the clinical features with Breast cancer patients. METHODS: In a case- control study, we have investigated 150 breast cancer patients and 300 age and ethnically matched healthy controls for duration of 3 years from North India. Promoter polymorphisms of tumor necrosis factor gene (TNF-α -308 G/A and TNF-ß +252 A/G) were genotyped using allele specific oligonucleotide polymerase chain reaction ASO and restriction fragment length polymorphism (PCR-RFLP). The associations were evaluated by calculating the pooled odds ratio (OR) with 95% confidence interval (95% CI) using SPSS. RESULTS: Patients with different clinico-pathological variables and healthy controls were analyzed. Significant association was observed in A allele of TNF-α -308 G/A in breast cancer patients as compared to healthy controls (p<0.0001). However, no association was seen in TNF-ß +252 A/G both at genotypic and allelic level. The GG genotype of TNF-ß +252A/G is higher in grades III (p<0.01) patients. CONCLUSION: Our results suggest that TNF-α-308G/A polymorphism showed significant association with breast cancer patients.

Clinical relevance of antibody development in renal transplantation.

The detection and characterization of anti-HLA antibodies and the clinical impact of their appearance following renal transplantation are areas of immense interest. In particular, de novo development of donor-specific antibodies (DSA) has been associated with acute and chronic antibody-mediated graft rejection (AMR). Recently, methods for antibody detection have evolved remarkably from conventional cell-based assays to advanced solid phase systems. These systems have revolutionized the art of defining clinically relevant antibodies that are directed toward a renal graft. While anti-HLA DSAs have been widely associated with poor graft survival, the role of non-HLA antibodies, particularly those directed against endothelial cells, is beginning to be realized. Appreciation of the mechanisms underlying T cell recognition of alloantigens has generated great interest in the use of synthetic peptides to prevent graft rejection. Hopefully, continued progress in unraveling the molecular mechanisms of graft rejection and posttransplant monitoring of antibodies using highly sensitive testing systems will prove beneficial to immunological risk assessment and early prediction of renal allograft failure.

Post transplant development of MICA and anti-HLA antibodies is associated with acute rejection episodes and renal allograft loss.

This study was undertaken with the primary aim of analyzing the clinical relevance of posttransplant appearance of anti-human leukocyte antigen (HLA) and major histocompatibility (MHC) class I related chain A (MICA) antibodies in response to live related donor (LRD) renal transplantation. A total of 185 consecutive post renal transplant recipient serum samples were analyzed for the detection of anti-HLA by enzyme-linked immunoabsorbent assay (ELISA) and MICA antibodies using Luminex techniques. Patients with IgG HLA class I antibodies had more acute rejection episodes compared to the negative group (67% vs. 20%, chi(2) = 7.95, p = 0.005) and also had poor graft survival (44% vs 86%, chi(2) = 6.67, p = 0.01). Similarly, patients with anti-HLA class II antibodies also had significantly lower graft survival and a higher number of rejection episodes as compared to the antibody negative group (p = 0.002 and p = 0.000, respectively). Following transplantation, 30 patients (16%) developed antibodies against any of the MICA alleles (MICA*001, MICA*002, MICA*004, MICA*008, or MIC*009). The graft survival was significantly compromised in these patients as compared to the negative group (60% vs 86%, chi(2) = 10.26, p = 0.001). Further, patients carrying both antibodies (MICA+/HLA+) were the worst affected and showed significantly poor graft survival as compared to the MICA-/HLA- group (17% vs 89%, chi(2) = 19.63, p = 0.000). Similarly, patients with only MICA antibodies or those with only HLA antibodies also had significantly lower graft survival and a higher number of acute rejection episodes (p = 0.035 and p = 0.001, respectively) as compared to the nonsensitized group. The study illustrates that posttransplant monitoring of antibodies to both MICA as well as HLA could be an important prognostic marker in renal transplant subjects.