Graduate Program of Pharmaceutical Innovation, Federal University of Amapá, Macapá-AP 68902-280, Brazil.
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá-AP 68902-280, Brazil.
Molecules. 2019 Apr 15;24(8):1476. doi: 10.3390/molecules24081476.
Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.
炎症是一种涉及细胞和分子成分的复杂反应，是对特定侵袭的非特异性反应。将科学和技术创新作为一种研究工具，结合信息学、生物技术、化学和生物学等多学科知识，对于优化药物设计的时间和降低成本至关重要。因此，这些计算机技术的整合使得可以寻找具有更好的药代动力学和毒理学特性的新型抗炎药物，与商业上使用的药物相比。这项计算机研究使用分子对接评估了两种苯甲酰丙酸衍生物（MBPA 和 DHBPA）的抗炎潜力，并通过分子动力学评估了它们的热力学特性，此外还预测了口服生物利用度、生物活性和毒性。根据我们的预测，这里提出的衍生物具有抑制人源和鼠源 COX-2 的潜力，因为它们与对照化合物（布洛芬）具有相似的相互作用。布洛芬显示出肝毒性（在人、鼠和大鼠中；毒理基团 2-芳基乙酸或 3-芳基丙酸）和胃肠道刺激（在人、鼠和大鼠中；毒理基团α-取代丙酸或酯）的毒性预测，这与文献数据一致，也证实了 DEREK 10.0.2 程序的效率。此外，与商业化合物相比，所提出的化合物被预测具有良好的口服生物利用度、低毒性（LD<700mg/kg）和安全性。因此，有必要进行进一步的研究来证实这些化合物的抗炎潜力。
