A Mapping of Drug Space from the Viewpoint of Small Molecule Metabolism

Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the “effect space” comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism

استبداد الأفق المعرفي – أساطير العمالقة و ثبات الخيال الرؤيوي

يتناول هذا البحث بعض العبارات الأساطورية المجازية المعهودة الناقلة للفكر اليهودي و المسيحي الرؤيوي و مصادر الصور المجازية التي تسود الخطاب في التعابير الحديثة عن العنف المبرر دينيا. يعتبر إطلاق صفة الشيطان على الخصوم و فكرة الحرب الكونية الموخهة إلهيا بالنسبة لبعض المتمسكين بالديانات التوحيدية عناصر لنمذج روائي يؤطر الصراعات الحالية بتعابير أخروية (تتسم بالإيمان بالآخرة في الأديان التوحيدية) و تشاهد سوابق هذه العبارات المجازية في المهمة التي تؤديها أسطورة توراتية عن انتصار شبه تاريخي، و لا حقا بطريقة مؤثرة في 1 أخنوز، و ينظر إلى هذه التكرار للأساطورة في الأخروية التي تنطوي عليها الأديان التوحيدية – كرد فعل على الأزمات المتصورة من منظو Hanse Blumeberg في أن الأسطورة هي تعبير عن التخفيف المتواصل من حدة مايدعوه استناد الواقع – ألا و هو الوقوف أمام عالم حياتي يتخطى سيطرة الفرد. تساعد صفات الأسطورة النمذ جية المبهمة الخيال الذي تعمر به الأديان التوحيدية على مصارعة الحوادث الطارئة في الخبرة التاريخية التي غالبا ما تكون مثيرة للرهبة

Optimal Design for Estimating Parameters of the 4-Parameter Hill Model

Many drug concentration-effect relationships are described by nonlinear sigmoid models. The 4-parameter Hill model, which belongs to this class, is commonly used. An experimental design is essential to accurately estimate the parameters of the model. In this report we investigate properties of D-optimal designs. D-optimal designs minimize the volume of the confidence region for the parameter estimates or, equivalently, minimize the determinant of the variance-covariance matrix of the estimated parameters. It is assumed that the variance of the random error is proportional to some power of the response. To generate D-optimal designs one needs to assume the values of the parameters. Even when these preliminary guesses about the parameter values are appreciably different from the true values of the parameters, the D-optimal designs produce satisfactory results. This property of D-optimal designs is called robustness. It can be quantified by using D-efficiency. A five-point design consisting of four D-optimal points and an extra fifth point is introduced with the goals to increase robustness and to better characterize the middle part of the Hill curve. Four-point D-optimal designs are then compared to five-point designs and to log-spread designs, both theoretically and practically with laboratory experiments