Abstract

Human African trypanosomiasis (HAT) or sleeping sickness like infections remain a serious health concern around the globe due to unavailability of safe and potential drugs for their treatment. Moreover, developing safe, potential and highly specific target based treatments is still a challenge for present drug discovery programs. A series of pyrazole based sulfonamides are identified as an inhibitor of Trypanosoma brucei N-myristoyltransferase (TbNMT). In the present manuscript, we have developed robust and reliable QSAR models by using the balance of correlation method in CORAL software. The chemical structures are represented by simplified molecular input line entry system (SMILES). The significance of the index of ideality correlation (IIC) with applicability domain (AD) is also studied at depth. The models developed by considering the index of ideality of correlation (IIC) were found to statistically more significant and robust. One QSAR model with best $R_{\mathit{calibration}}^2$ = 0.8638 for split 2 was considered as the leading model. A greater value of cRp² i.e. 0.5 for all models in Y-randomization test showed the robustness of developed models. The outliers and promoters of increase and decrease of endpoint were also extracted independently from the leading models. The mechanistic interpretation of developed models explains the role of different structural attributes in predicting the pIC₅₀ of pyrazole sulfonamides extracted from the crystal structure of Leishmania major N-myristoyltransferase (NMT) along with co-crystallized myristoyl-CoA and ligands NMT106, NMT157, NMT187 and NMT236 (PDB ID: 4A2Z, 4A30, 4A32, 2WSA).

Communicated by Ramaswamy H. Sarma

摘要

由于无法获得安全和潜在的治疗药物，非洲人类锥虫病 (HAT) 或昏睡病等感染仍然是全球严重的健康问题。此外，开发安全、潜在和高度特异性的靶向治疗仍然是当前药物发现计划的挑战。一系列基于吡唑的磺胺被鉴定为布氏锥虫 N的抑制剂-肉豆蔻酰基转移酶 (TbNMT)。在本手稿中，我们通过使用 CORAL 软件中的相关性平衡方法开发了稳健可靠的 QSAR 模型。化学结构由简化的分子输入线输入系统 (SMILES) 表示。还深入研究了理想相关性指数 (IIC) 与适用性域 (AD) 的重要性。发现通过考虑相关性理想指数 (IIC) 开发的模型在统计上更显着和稳健。一种具有最佳性能的 QSAR 模型${\mathrm{电阻}}_{\mathit{校准}}^2$= 0.8638 for split 2 被认为是领先的模型。较大的 cRp ² 值，即Y 随机化测试中所有模型的 0.5 表明开发模型的稳健性。端点增加和减少的异常值和促进因素也从领先模型中独立提取。已开发模型的机械解释解释了不同结构属性在预测从利什曼原虫主要 N-肉豆蔻酰转移酶 (NMT) 的晶体结构中提取的吡唑磺酰胺的 pIC ₅₀以及共结晶肉豆蔻酰辅酶 A 和配体 NMT106、NMT157、NMT187 的作用和 NMT236（PDB ID：4A2Z、4A30、4A32、2WSA）。

由 Ramaswamy H. Sarma 交流