ABSTRACT
Raf proto-oncogene serine/threonine kinase 1 (RAF1 or c-Raf) is a serine/threonine protein kinase crucial in regulating cell growth, differentiation, and survival. Any disruption or overexpression of RAF1 can result in neoplastic transformation and other disorders such as cardiomyopathy, Noonan syndrome, leopard syndrome, etc. RAF1 has been identified as a potential therapeutic target in drug development against various complex diseases, including cancer, due to its remarkable role in disease progression. Here, we carried out a multitier virtual screening study involving different in-silico approaches to discover potential inhibitors of RAF1. After applying the Lipinski rule of five, we retrieved all phytocompounds from the IMPPAT database based on their physicochemical properties. We performed a molecular docking-based virtual screening and got top hits with the best binding affinity and ligand efficiency. Then we screened out the selected hits using the PAINS filter, ADMET properties, and other druglike features. Eventually, PASS evaluation identifies two phytocompounds, Moracin C and Tectochrysin, with appreciable anti-cancerous properties. Finally, all-atom molecular dynamics simulation (MDS) followed by interaction analysis was performed on the elucidated compounds in complex with RAF1 for 200 ns to investigate their time-evolution dynamics and interaction mechanism. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and Dynamical Cross-Correlation Matrix (DCCM) analyses then followed these results from the simulated trajectories. According to the results, the elucidated compounds stabilize the RAF1 structure and lead to fewer conformational alterations. The results of the current study indicated that Moracin C and Tectochrysin could serve as potential inhibitors of RAF1 after required validation.Communicated by Ramaswamy H. Sarma.
Subject(s)
Benzofurans , Molecular Dynamics Simulation , Protein Serine-Threonine Kinases , Stilbenes , Protein Serine-Threonine Kinases/chemistry , Molecular Docking Simulation , Drug Development , SerineABSTRACT
We discuss two cases of reactive focal myositis that had different clinical presentations but responded well to conservative management. These cases demonstrate that reactive myositis can present acutely but resolves quickly with expectant treatment and has a favourable prognosis.
Subject(s)
Myositis/diagnosis , Acute Disease , Adult , C-Reactive Protein/metabolism , Creatine Kinase/metabolism , Diagnosis, Differential , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Remission, Spontaneous , Watchful WaitingABSTRACT
This is a case of a 65-year-old man with seropositive erosive rheumatoid arthritis (RA), well controlled on methotrexate, sulfasalazine, low-dose prednisolone and monthly infusions of tocilizumab. He presented with a 3-week history of pain and swelling in his left knee, gradually increasing in severity with an inability to bear weight. He was systemically well with normal vital signs. Examination confirmed an effusion and aspiration was turbid in appearance. C reactive protein (CRP) was normal. He was treated empirically with antibiotics. Synovial fluid and blood cultures confirmed Staphylococcus aureus infection. He completed a 6 weeks course of antibiotics with complete resolution of symptoms. Throughout the treatment his CRP remained normal which is likely to have been the result of prior treatment with tocilizumab.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antirheumatic Agents/administration & dosage , Arthritis, Infectious/blood , Arthritis, Rheumatoid/drug therapy , C-Reactive Protein/metabolism , Staphylococcal Infections/blood , Aged , Anti-Bacterial Agents/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antirheumatic Agents/adverse effects , Arthritis, Infectious/drug therapy , Arthritis, Infectious/etiology , Arthritis, Rheumatoid/blood , Biomarkers/analysis , Biomarkers/metabolism , Humans , Knee Joint , Male , Methotrexate/administration & dosage , Prednisolone/administration & dosage , Risk Assessment , Sensitivity and Specificity , Severity of Illness Index , Staphylococcal Infections/drug therapy , Staphylococcal Infections/etiology , Sulfasalazine/administration & dosage , Treatment OutcomeABSTRACT
A 48-year-old immunosuppressed woman presented to a rheumatology follow-up clinic after suffering from herpes zoster infection. She had manifestations of foot drop 3 months after the initial infection. She was diagnosed with motor radiculopathy following herpes zoster infection that was effectively managed by physiotherapy and amitriptyline.
Subject(s)
Gait Disorders, Neurologic/virology , Herpes Zoster/complications , Radiculopathy/virology , Amitriptyline/therapeutic use , Analgesics, Non-Narcotic/therapeutic use , Female , Gait Disorders, Neurologic/therapy , Humans , Middle Aged , Physical Therapy Modalities , Radiculopathy/therapyABSTRACT
Wegener's Granulomatosis (WG) is a systemic vasculitis typically associated with antineutrophil cytoplasmic antibodies (ANCAs). A small proportion of patients are ANCA negative, however, and this is more commonly found in individuals with disease limited to the ears, nose, throat, and lungs, who do not have renal involvement. Rituximab is a monoclonal anti-CD20 antibody that has been demonstrated to be effective in the treatment of autoantibody-associated rheumatic diseases, including systemic WG. We report the case of a patient with ANCA-negative WG who responded well to rituximab, illustrating that even in the absence of detectable autoantibodies, B-cell depletion can be effective.
