Department of Pharmacoinformatics, National Institute of Pharmaceutical Education & Research, SAS Nagar, Nagar, Punjab 160062, India.
Future Med Chem. 2014 Apr;6(6):605-16. doi: 10.4155/fmc.14.27.
Direct InhA inhibitors, which interact with the substrate-binding loop (SBL) and order it into a closed state, are thought to be potential anti-multidrug-resistant tuberculosis molecules. Thus, developing parameters to distinguish between the open and closed state of SBL can help in screening the potent inhibitors with loop ordering properties.
We report empirical parameters to differentiate the 'open' and 'closed' conformation of SBL by comprehensive ana-lysis of InhA crystal structures. The 'open' state of SBL was observed with intra- and inter-loop H-bonding within the residues pair, G205-G208 and L207-I105, respectively, while the 'closed' conformation is found with H-bonding within the residues pair: L207-E210 and A206-I105. Moreover, potent inhibitors (IC50, 5.3-5160 nM) are observed to make hydrophobic interactions with residues of SBL, particularly with A198 in the structures with closed state of SBL.
The observed set of H-bonding pattern and hydrophobic contact with residues of SBL can be utilized as a filter to evaluate novel inhibitors for their SBL ordering properties and potencies using the molecular dynamic simulation in the virtual screening of direct InhA inhibitors.
直接作用于 InhA 的抑制剂与底物结合环（SBL）相互作用，并使其处于闭合状态，被认为是有潜力的抗多药耐药结核分子。因此，开发区分 SBL 开环和闭环状态的参数有助于筛选具有环序性质的有效抑制剂。
我们通过对 InhA 晶体结构的综合分析，报告了区分 SBL“开”和“闭”构象的经验参数。SBL 的“开”环状态观察到残基对 G205-G208 和 L207-I105 内的环内和环间氢键，而“闭”构象则观察到残基对 L207-E210 和 A206-I105 内的氢键。此外，观察到有效的抑制剂（IC50，5.3-5160 nM）与 SBL 的残基形成疏水相互作用，特别是在 SBL 处于闭环状态的结构中与 A198 形成疏水相互作用。
所观察到的 SBL 氢键模式和残基疏水接触的集合可以用作筛选新型抑制剂的筛选器，以评估其 SBL 排序性质和效力，方法是在直接 InhA 抑制剂的虚拟筛选中使用分子动力学模拟。
