Makki Almansour Nahlah
Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin 31991, Saudi Arabia.
Saudi Pharm J. 2023 Oct;31(10):101751. doi: 10.1016/j.jsps.2023.101751. Epub 2023 Aug 22.
Metastatic breast cancer is a prime health concern and leading health burden across the globe. Previous efforts have shown that protein-protein interaction between Metadherin and Staphylococcal nuclease domaincontaining 1 (SND1) promotes initiation of breast cancer, progression, therapy resistance and metastasis. Therefore, small drug molecules that can interrupt the Metadherin and SND1 interaction may be ideal to suppress tumor growth, metastasis and increases chemotherapy sensitivity of triple negative breast cancer. Here, in this study, structure based virtual screening was conducted against the reported active site of SND1 enzyme, which revealed three promising lead molecules from Asinex library. These compounds were; BAS_00381028, BAS_00327287, and BAS_01293454 with binding energy score -10.25 kcal/mol, -9.65 kcal/mol and -9.32 kcal/mol, respectively. Compared to control (5-chloro-2-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-8-yl)benzene-1-sulfonamide) the lead molecules showed robust hydrophilic and hydrophobic interactions with the enzyme and revealed stable docked conformation in molecular dynamics simulation. During the simulation time, the compounds reported stable dynamics with no obvious fluctuation in binding mode and interactions noticed. The mean root mean square deviation (RMSD) of BAS_00381028, BAS_00327287, and BAS_01293454 complexes were 1.87 Å, 1.75 Å, 1.34 Å, respectively. Furthermore, the MM/GBSA analysis was conduction on the simulation trajectories of complexes that unveiled binding energy score of -19.25 kcal/mol, -27.03 kcal/mol, -34.6 kcal/mol and -29.61 kcal/mol for control, BAS_00381028, BAS_00327287, and BAS_01293454, respectively. In MM/PBSA, the binding energy value of for control, BAS_00381028, BAS_00327287, and BAS_01293454 was -20.45 kcal/mol, -27.89 kcal/mol, -36.41 kcal/mol and -32.01 kcal/mol, respectively. Additionally, the compounds were classified as druglike and have favorable pharmacokinetic properties. The compounds were predicted as promising leads and might be used in experimental investigation to study their anti-SND1 activity.
转移性乳腺癌是全球主要的健康问题和主要的健康负担。先前的研究表明，Metadherin与含葡萄球菌核酸酶结构域1（SND1）之间的蛋白质-蛋白质相互作用促进乳腺癌的起始、进展、治疗抗性和转移。因此，能够中断Metadherin与SND1相互作用的小分子药物可能是抑制三阴性乳腺癌肿瘤生长、转移并提高化疗敏感性的理想选择。在此研究中，针对已报道的SND1酶活性位点进行了基于结构的虚拟筛选，从Asinex库中发现了三个有前景的先导分子。这些化合物分别是：BAS_00381028、BAS_00327287和BAS_01293454，结合能分数分别为-10.25千卡/摩尔、-9.65千卡/摩尔和-9.32千卡/摩尔。与对照（5-氯-2-甲氧基-N-([1,2,4]三唑并[1,5-a]吡啶-8-基)苯-1-磺酰胺）相比，这些先导分子与该酶表现出强大的亲水和疏水相互作用，并在分子动力学模拟中显示出稳定的对接构象。在模拟过程中，这些化合物表现出稳定的动力学，结合模式和相互作用没有明显波动。BAS_
