Alabbas Alhumaidi
Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia.
Biology (Basel). 2025 Aug 11;14(8):1030. doi: 10.3390/biology14081030.
The increasing number of resistant bacterial strains is reducing the effectiveness of antimicrobial drugs in preventing infections. It has been shown that resistant strains invade living organisms and cause a wide range of illnesses, leading to a surprisingly high death rate.
The present study aimed to identify novel dihydropteroate synthase (DHPS) inhibitors from using structure-based computational techniques.
This in silico study used various bioinformatics and cheminformatics approaches to find new DHPS inhibitors. It began by retrieving the crystal structure via PDB ID: 7L6P, followed by energy minimization. The DHPS enzyme was virtually screened against the CHEMBL library to target through enzyme inhibition. Then, absorption, distribution, metabolism, and excretion (ADME) analysis was performed to select the top hits. This process identified the top-10 hits. Additionally, imidazole (control) was used for comparative assessment. Furthermore, a 100 ns molecular dynamics simulation and post-simulation analyses were conducted. The docking results were validated through binding free energy calculations and entropy energy estimation approaches.
The docking results prioritized 10 compounds based on their binding scores, with a maximum threshold of -7 kcal/mol for selection. The ADME assessment shortlisted 3 out of 10 compounds: CHEMBL2322256, CHEMBL2316475, and CHEMBL2334441. These compounds satisfied Lipinski's rule of five and were considered drug-like. The identified inhibitors demonstrated greater stability and less deviation compared to the control (imidazole). The average RMSD stayed below 2 Å, indicating overall stability without major deviations in the DHPS-ligand complexes. Post-simulation analysis assessed the stability and interaction profiles of the complexes under physiological conditions. Hydrogen bonding analysis showed the control to be more stable than the three tested complexes. Increased salt bridge interactions suggested stronger electrostatic stabilization, while less alteration of the protein's secondary structure indicated better structural compatibility. These findings support the potential of these novel ligands as potent DHPS inhibitors. Binding energy estimates showed that CHEMBL2322256 was the most stable, with scores of -126.49 and -124.49 kcal/mol. Entropy calculations corroborated these results, indicating that CHEMBL2322256 had an estimated entropy of 8.63 kcal/mol.
The newly identified compounds showed more promising results compared to the control. While these compounds have potential as innovative drugs, further research is needed to confirm their effectiveness as anti-DHPS agents against antibiotic resistance and infections.
耐药细菌菌株数量的不断增加正在降低抗菌药物预防感染的有效性。研究表明，耐药菌株侵入生物体并引发多种疾病，导致惊人的高死亡率。
本研究旨在利用基于结构的计算技术从[具体来源未提及]中鉴定新型二氢蝶酸合酶（DHPS）抑制剂。
这项计算机模拟研究使用了各种生物信息学和化学信息学方法来寻找新的DHPS抑制剂。首先通过蛋白质数据银行（PDB）ID：7L6P检索晶体结构，随后进行能量最小化。针对CHEMBL库对DHPS酶进行虚拟筛选，以通过酶抑制作用靶向[具体靶点未提及]。然后进行吸收、分布、代谢和排泄（ADME）分析以选择最佳命中物。此过程确定了前10个命中物。此外，使用咪唑（对照）进行比较评估。此外还进行了100纳秒的分子动力学模拟和模拟后分析。通过结合自由能计算和熵能估计方法对对接结果进行验证。
对接结果根据结合分数对10种化合物进行了排序，选择的最大阈值为-7千卡/摩尔。ADME评估从10种化合物中筛选出3种：CHEMBL2322256、CHEMBL2316475和CHEMBL233444。这些化合物符合Lipinski的五规则，被认为具有类药物性质。与对照（咪唑）相比，鉴定出的抑制剂表现出更高的稳定性和更小的偏差。平均均方根偏差（RMSD）保持在2埃以下，表明DHPS-配体复合物总体稳定，无重大偏差。模拟后分析评估了复合物在生理条件下的稳定性和相互作用概况。氢键分析表明对照比三种测试复合物更稳定。盐桥相互作用增加表明静电稳定作用更强，而蛋白质二级结构变化较小表明结构相容性更好。这些发现支持了这些新型配体作为有效DHPS抑制剂的潜力。结合能估计表明CHEMBL2322256最稳定，分数分别为-126.49和-124.49千卡/摩尔。熵计算证实了这些结果，表明CHEMBL2322256的估计熵为8.63千卡/摩尔。
与对照相比，新鉴定的化合物显示出更有前景的结果。虽然这些化合物有作为创新药物的潜力，但需要进一步研究以确认它们作为抗DHPS剂对抗抗生素耐药性和[具体感染未提及]感染的有效性。
