Roy Sudeep, Kumar Akhil, Baig Mohd Hassan, Masařík Michal, Provazník Ivo
Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology Technická 12, 61200 Brno, Czech Republic.
Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Methods. 2015 Jul 15;83:105-10. doi: 10.1016/j.ymeth.2015.04.021. Epub 2015 Apr 25.
Metallothionein-III (MT-III) displays neuro-inhibitory activity and is involved in the repair of neuronal damage. An altered expression level of MT-III suggests that it could be a mitigating factor in Alzheimer's disease (AD) neuronal dysfunction. Currently there are limited marketed drugs available against MT-III. The inhibitors are mostly pseudo-peptide based with limited ADMET. In our present study, available database InterBioScreen (natural compounds) was screened out for MT-III. Pharmacodynamics and pharmacokinetic studies were performed. Molecular docking and simulations of top hit molecules were performed to study complex stability.
Study reveals potent selective molecules that interact and form hydrogen bonds with amino acids Ser-6 and Lys-22 are common to established melatonin inhibitors for MT-III. These include DMHMIO, MCA B and s27533 derivatives. The ADMET profiling was better with comparable interaction energy values. It includes properties like blood brain barrier, hepatotoxicity, druggability, mutagenicity and carcinogenicity. Molecular dynamics studies were performed to validate our findings.
金属硫蛋白III（MT-III）具有神经抑制活性，并参与神经元损伤的修复。MT-III表达水平的改变表明它可能是阿尔茨海默病（AD）神经元功能障碍的一个缓解因素。目前针对MT-III的上市药物有限。这些抑制剂大多是基于伪肽的，其药物代谢动力学性质有限。在我们目前的研究中，从可用的InterBioScreen数据库（天然化合物）中筛选出了针对MT-III的化合物。进行了药效学和药代动力学研究。对筛选出的顶级分子进行了分子对接和模拟，以研究复合物的稳定性。
研究发现了一些有效的选择性分子，它们与已确定的MT-III褪黑素抑制剂一样，能与丝氨酸-6和赖氨酸-22氨基酸相互作用并形成氢键。这些分子包括DMHMIO、MCA B和s27533衍生物。它们的药物代谢动力学性质分析结果较好，且具有相当的相互作用能值。这包括血脑屏障、肝毒性、成药性、致突变性和致癌性等性质。进行了分子动力学研究以验证我们的发现。
