Muneeshwari Arasu, Sampath Natarajan
Chemical Biology Lab, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, 613401, India.
Mol Divers. 2025 Jul 24. doi: 10.1007/s11030-025-11304-5.
A flavoenzyme, UDP-galactopyranose mutase (UGM), serves as a pivotal enzyme catalysing the conversion of UDP-galactopyranose (galP) into UDP-galactofuranose (galF), a metabolite exclusively present in pathogenic microorganisms, including filarial parasites. The galF plays a critical role in various pathogenic processes, like cell wall biosynthesis, virulence enhancement, and cuticle formation in filarial parasites. Notably, the absence of galF in humans renders, UGM an attractive and promising drug target for developing potent antifilarial therapeutics. In this study, we employed advanced bioinformatics approaches to identify effective antifilarial drug candidates. The UGM enzyme from Brugia malayi (BmUGM) was meticulously modelled and subsequently utilized for molecular docking studies against 20 triazolothiadiazine analogues using the AutoDock program. Among these, eight compounds exhibiting high binding affinities, ranging from - 8.7 to - 10.5 kcal/mol, were selected for further protein-ligand MD simulations. Post-simulation analyses, encompassing MM-PBSA and binding free energy decomposition, demonstrated that two triazolothiadiazine analogues, namely D4 and D8, exhibited exceptionally high binding free energies of - 29.76 kcal/mol and - 27.50 kcal/mol, respectively. These values exceeded the binding free energy of the natural substrate galP, which was calculated at - 20.01 kcal/mol. Furthermore, binding free energy decomposition analysis pinpointed critical binding site residues Tyr168, Trp184, Tyr326, Tyr335, Arg336, Tyr405, and Gln475 as essential mediators of the protein-ligand interactions. Additionally, ADMET and DFT quantum mechanical calculations confirmed that the triazolothiadiazine analogues exhibit low toxicity profiles and favourable chemical reactivity. Based on these findings, we propose that the identified ligand molecules hold potential as potent inhibitors of BmUGM, with broad-spectrum efficacy against all life stages of filarial parasites.
一种黄素酶，尿苷二磷酸半乳糖吡喃糖变位酶（UGM），是催化尿苷二磷酸半乳糖吡喃糖（galP）转化为尿苷二磷酸半乳糖呋喃糖（galF）的关键酶，galF是一种仅存在于包括丝虫寄生虫在内的致病微生物中的代谢物。galF在各种致病过程中起关键作用，如丝虫寄生虫的细胞壁生物合成、毒力增强和表皮形成。值得注意的是，人类体内不存在galF，这使得UGM成为开发有效抗丝虫治疗药物的一个有吸引力且有前景的药物靶点。在本研究中，我们采用先进的生物信息学方法来鉴定有效的抗丝虫药物候选物。对马来布鲁线虫（BmUGM）的UGM酶进行了精细建模，随后使用AutoDock程序针对20种三唑并噻二嗪类似物进行分子对接研究。其中，选择了8种具有高结合亲和力的化合物，范围为 -8.7至 -10.5千卡/摩尔，用于进一步的蛋白质 - 配体分子动力学模拟。模拟后分析，包括MM - PBSA和结合自由能分解，表明两种三唑并噻二嗪类似物，即D4和D8，分别表现出异常高的结合自由能，为 -29.76千卡/摩尔和 -27.50千卡/摩尔。这些值超过了天然底物galP的结合自由能，其计算值为 -20.01千卡/摩尔。此外，结合自由能分解分析确定关键结合位点残基Tyr168、Trp184、Tyr326、Tyr335、Arg336、Tyr405和Gln475是蛋白质 - 配体相互作用的重要介导者。此外，ADMET和DFT量子力学计算证实三唑并噻二嗪类似物具有低毒性特征和良好的化学反应性。基于这些发现，我们提出所鉴定的配体分子具有作为BmUGM有效抑制剂的潜力，对丝虫寄生虫的所有生命阶段具有广谱疗效。
