The Use of Pseudo-Equilibrium Constant Affords Improved QSAR Models of Human Plasma Protein Binding

PURPOSE: To develop accurate in silico predictors of Plasma Protein Binding (PPB). METHODS: Experimental PPB data were compiled for over 1,200 compounds. Two endpoints have been considered: (1) fraction bound (%PPB); and (2) the logarithm of a pseudo binding constant (lnKa) derived from %PPB. The latter metric was employed because it reflects the PPB thermodynamics and the distribution of the transformed data is closer to normal. Quantitative Structure-Activity Relationship (QSAR) models were built with Dragon descriptors and three statistical methods. RESULTS: Five-fold external validation procedure resulted in models with the prediction accuracy (R(2)) of 0.67±0.04 and 0.66±0.04, respectively, and the mean absolute error (MAE) of 15.3±0.2% and 13.6±0.2%, respectively. Models were validated with two external datasets: 173 compounds from DrugBank, and 236 chemicals from the US EPA ToxCast project. Models built with lnKa were significantly more accurate (MAE of 6.2–10.7%) than those built with %PPB (MAE of 11.9–17.6%) for highly bound compounds both for the training and the external sets. CONCLUSION: The pseudo binding constant (lnKa) is more appropriate for characterizing PPB binding than conventional %PPB. Validated QSAR models developed herein can be applied as reliable tools in early drug development and in chemical risk assessment

Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS)

Neuromyelitis optica (NMO, Devic's syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals