利用计算研究从头设计组织蛋白酶B1抑制剂作为潜在的抗血吸虫病药物
De Novo Design of Cathepsin B1 Inhibitors as Potential Anti-Schistosomal Agents Using Computational Studies.
作者信息
Alzain Abdulrahim A, Elbadwi Fatima A
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan.
出版信息
Adv Appl Bioinform Chem. 2022 Aug 1;15:29-41. doi: 10.2147/AABC.S361626. eCollection 2022.
BACKGROUND
Schistosomiasis is the world's second most devastating disease after malaria and the leading cause of disease and mortality for more than 200 million people in developing countries. Cysteine proteases, in particular SmCB1, are the most well-researched biological targets for this disorder.
OBJECTIVE
To apply computational techniques to design new antischistosomal agents against SmCB1 protein with favorable pharmacokinetic properties.
METHODS
The smCB1 receptor-based pharmacophore model was created and used to screen 567,000 fragments from the Enamine library. The best scoring fragments have been linked to build novel compounds that were subjected to molecular docking, MM-GBSA free energy estimation, ADME prediction, and molecular dynamics.
RESULTS
A seven-point pharmacophore hypothesis ADDDRRR was created. The developed hypothesis was used to screen 1.3 M fragment conformations. Among them, 23,732 fragments matched the hypothesis and screened against the protein. The top 50 fragments were used to design new 7745 compounds using the Breed ligand panel which were subjected to docking and MMGBSA binding energy. This led to the identification of 10 compounds with better docking scores (-8.033- -7.483 kcal/mol) and lower-bound free energies (-58.49 - -40.02 kcal/mol) compared to the reference bound ligand. Most of the designed compounds demonstrated good drug-like properties. Concerning Molecular dynamics (MD) simulation results, a low root mean square deviation (RMSD) range (0.25-1.2 Å) was found for the top 3 complexes which indicated their stability.
CONCLUSION
We identified compounds that could be potential candidates in the search for novel inhibitors by targeting SmCB1 utilizing various computational tools. Three newly designed compounds namely breed 1, 2, and 3 showed promising affinity to the target as well as favorable drug-like properties which might be considered potential anti-schistosomal agents.
背景
血吸虫病是仅次于疟疾的全球第二大致残性疾病，也是发展中国家超过2亿人患病和死亡的主要原因。半胱氨酸蛋白酶，特别是SmCB1，是针对这种疾病研究最为深入的生物学靶点。
目的
应用计算技术设计针对SmCB1蛋白的具有良好药代动力学性质的新型抗血吸虫药物。
方法
构建基于smCB1受体的药效团模型，并用于筛选来自Enamine库的567,000个片段。对得分最高的片段进行连接以构建新型化合物，这些化合物经过分子对接、MM-GBSA自由能估计、ADME预测和分子动力学研究。
结果
创建了一个七点药效团假设ADDRRR。利用所建立的假设筛选了130万个片段构象。其中，23,732个片段符合该假设并针对蛋白质进行筛选。使用Breed配体面板，前50个片段用于设计7745种新化合物，这些化合物经过对接和MMGBSA结合能研究。与参考结合配体相比，这导致鉴定出10种具有更好对接分数（-8.033--7.483 kcal/mol）和更低结合自由能（-58.49--40.02 kcal/mol）的化合物。大多数设计的化合物表现出良好的类药性质。关于分子动力学（MD）模拟结果，前3种复合物的均方根偏差（RMSD）范围较低（0.25-1.2 Å），表明它们的稳定性。
结论
我们利用各种计算工具，通过靶向SmCB1鉴定出了可能成为新型抑制剂的化合物。三种新设计的化合物，即breed 1、2和3，对靶点表现出有前景的亲和力以及良好的类药性质，可能被视为潜在的抗血吸虫药物。
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