El Haddoumi Ghyzlane, Mansouri Mariam, Kourou Jouhaina, Belyamani Lahcen, Ibrahimi Azeddine, Kandoussi Ilham
Biotechnology Lab (MedBiotech), Bioinova Research Center, Rabat Medical and Pharmacy School, Mohammed V University in Rabat, Rabat, Morocco.
Mohammed VI Center For Research and Innovation (CM6), Rabat, Morocco.
Bioinform Biol Insights. 2024 May 28;18:11779322241257039. doi: 10.1177/11779322241257039. eCollection 2024.
Tuberculosis (TB) remains a global health challenge with the emergence of drug-resistant Mycobacterium tuberculosis variants, necessitating innovative drug molecules. One potential target is the cell wall synthesis enzyme decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), crucial for virulence and survival. This study employed virtual screening of 111 Protein Data Bank (PDB) database molecules known for their inhibitory biological activity against DprE1 with known IC50 values. Six compounds, PubChem ID: 390820, 86287492, 155294899, 155522922, 162651615, and 162665075, exhibited promising attributes as drug candidates and validated against clinical trial inhibitors BTZ043, TBA-7371, PBTZ169, and OPC-167832. Concurrently, this research focused on DprE1 mutation effects using molecular dynamic simulations. Among the 10 mutations tested, C387N significantly influenced protein behavior, leading to structural alterations observed through root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA) analysis. Ligand 2 (ID: 390820) emerged as a promising candidate through ligand-based pharmacophore analysis, displaying enhanced binding compared with reference inhibitors. Molecular dynamic simulations highlighted ligand 2's interaction with the C387N mutation, reducing fluctuations, augmenting hydrogen bonding, and influencing solvent accessibility. These collective findings emphasize ligand 2's efficacy, particularly against severe mutations, in enhancing protein-ligand complex stability. Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2's potential for advanced drug development strategies.
随着耐药性结核分枝杆菌变体的出现，结核病（TB）仍然是一项全球卫生挑战，因此需要创新的药物分子。一个潜在的靶点是细胞壁合成酶十聚异戊二烯磷酸基-β-D-核糖2'-表异构酶（DprE1），它对毒力和生存至关重要。本研究对111个蛋白质数据库（PDB）分子进行了虚拟筛选，这些分子以其对DprE1具有已知IC50值的抑制生物活性而闻名。六种化合物，PubChem ID：390820、86287492、155294899、155522922、162651615和162665075，表现出作为候选药物的有前景的特性，并针对临床试验抑制剂BTZ043、TBA-7371、PBTZ169和OPC-167832进行了验证。同时，本研究使用分子动力学模拟关注DprE1突变的影响。在测试的10个突变中，C387N显著影响蛋白质行为，通过均方根偏差（RMSD）、均方根波动（RMSF）、回转半径（Rg）和溶剂可及表面积（SASA）分析观察到结构改变。通过基于配体的药效团分析，配体2（ID：390820）成为一个有前景的候选物，与参考抑制剂相比显示出增强的结合。分子动力学模拟突出了配体2与C387N突变的相互作用，减少了波动，增强了氢键，并影响了溶剂可及性。这些综合发现强调了配体2在增强蛋白质-配体复合物稳定性方面的功效，特别是针对严重突变。综合计算和药效团方法为候选药物及其在复杂蛋白质环境中的相互作用提供了有价值的见解。本研究为针对耐药结核病的靶向干预奠定了战略基础，突出了配体2在先进药物开发策略中的潜力。
