South African National Bioinformatics Institute (SANBI), SA Medical Research Council Bioinformatics Unit, University of the Western Cape, Private Bag X17, Bellville, 7535, Cape Town, South Africa.
Sci Rep. 2019 Mar 13;9(1):4405. doi: 10.1038/s41598-019-40621-7.
Rv2984 is one of the polyphosphate kinases present in Mycobacterium tuberculosis involved in the catalytic synthesis of inorganic polyphosphate, which plays an essential role in bacterial virulence and drug resistance. Consequently, the structure of Rv2984 was investigated and an 18 membered compound library was designed by altering the scaffolds of computationally identified inhibitors. The virtual screening of these altered inhibitors was performed against Rv2984 and the top three scoring inhibitors were selected, exhibiting the free energy of binding between 8.2-9 kcal mol and inhibition constants in the range of 255-866 nM. These selected molecules showed relatively higher binding affinities against Rv2984 compared to the first line drugs Isoniazid and Rifampicin. Furthermore, the docked complexes were further analyzed in explicit water conditions using 100 ns Molecular Dynamics simulations. Through the assessment of obtained trajectories, the interactions between the protein and selected inhibitors including first line drugs were evaluated using MM/PBSA technique. The results validated the higher efficiency of the designed molecules compared to 1 line drugs with total interaction energies observed between -100 kJ mol and -1000 kJ mol. This study will facilitate the process of drug designing against M. tuberculosis and can be used in the development of potential therapeutics against drug-resistant strains of bacteria.
Rv2984 是分枝杆菌中存在的多磷酸盐激酶之一，参与无机多磷酸盐的催化合成，在细菌毒力和耐药性中起重要作用。因此，研究了 Rv2984 的结构，并通过改变计算鉴定的抑制剂的支架设计了一个 18 元化合物库。对这些改变的抑制剂进行了针对 Rv2984 的虚拟筛选，选择了得分最高的三种抑制剂，它们的结合自由能在 8.2-9 kcal/mol 之间，抑制常数在 255-866 nM 范围内。与一线药物异烟肼和利福平相比，这些选择的分子对 Rv2984 表现出相对较高的结合亲和力。此外，还在明确的水条件下使用 100 ns 分子动力学模拟对对接复合物进行了进一步分析。通过评估获得的轨迹，使用 MM/PBSA 技术评估了蛋白质与所选抑制剂（包括一线药物）之间的相互作用。结果验证了设计分子比一线药物具有更高的效率，观察到的总相互能在-100 kJ/mol 到-1000 kJ/mol 之间。这项研究将有助于针对结核分枝杆菌的药物设计过程，并可用于开发针对耐药菌的潜在治疗方法。
