Department of Genetic Engineering and Biotechnology, University of Dhaka, Bangladesh.
J Mol Graph Model. 2021 Jan;102:107774. doi: 10.1016/j.jmgm.2020.107774. Epub 2020 Oct 8.
Amongst the anti-TNF-α therapy for rheumatoid arthritis and other autoimmune diseases, Adalimumab mAb is one of the best candidates. However, several risk factors are found to be associated with higher doses. Improvement of the binding properties will therefore significantly increase its therapeutic efficacy, reduce the dosage requirements, and ultimately the associated toxicity and treatment cost. Here, we proposed a systematic in silico approach of finding newer mAb variants with improved binding properties. Using various bioinformatics tools, we have identified the significant amino acid residues on Adalimumab mAb. Next, we searched for the suitability of the other residues for mutating the significant residues and from the combinations of suitable mutations, variants were designed. To find the most significant ones, binding properties of the variants were compared with the wild type Adalimumab mAb using molecular docking scrutiny and molecular dynamics simulation. Finally, structural properties between the variant and wild type were analyzed. We have identified the six most significant residues on Adalimumab mAb involved in the antigen-antibody interactions. Using the suitable mutations replacing each of these residues, we have modeled 143 variants. From several docking analyses, we have found five significant variants and after molecular dynamics simulation, one most significant variant with improved binding affinity was identified whose structural properties are similar to the wild type Adalimumab mAb. Designed variant from this study, may provide newer insights on the structure-based affinity improvements of monoclonal antibodies and likewise modifications of the Fc region will also improve the therapeutic effector functions of antibodies too.
在类风湿关节炎和其他自身免疫性疾病的抗 TNF-α 治疗中，阿达木单抗 mAb 是最佳候选药物之一。然而，已经发现一些风险因素与更高剂量相关。因此，改善结合特性将显著提高其治疗效果，降低剂量要求，并最终降低相关毒性和治疗成本。在这里，我们提出了一种系统的计算方法，以寻找具有改善结合特性的新型 mAb 变体。我们使用各种生物信息学工具，确定了阿达木单抗 mAb 上的重要氨基酸残基。接下来，我们寻找其他残基适合突变重要残基的情况，并从合适的突变组合中设计变体。为了找到最重要的变体，我们使用分子对接仔细检查和分子动力学模拟比较了变体的结合特性与野生型阿达木单抗 mAb。最后，分析了变体和野生型之间的结构特性。我们确定了阿达木单抗 mAb 上涉及抗原 - 抗体相互作用的六个最重要的残基。使用合适的突变替换每个这些残基，我们已经构建了 143 个变体。通过几次对接分析，我们发现了五个重要的变体，经过分子动力学模拟，确定了一个具有改善结合亲和力的最重要变体，其结构特性与野生型阿达木单抗 mAb 相似。本研究设计的变体，可能为基于结构的单克隆抗体亲和力改善提供新的见解，同样地，Fc 区域的修饰也将改善抗体的治疗效应功能。
