SilicoScientia Private Limited, Nagananda Commercial Complex, No. 07/3, 15/1, 18th Main Road, Jayanagar 9th Block, Bengaluru, 5600413, India.
Department of Bioinformatics, Rajiv Gandhi Institute of IT and Biotechnology, Bharati Vidyapeeth Deemed to be University, Pune-Satara Road, Pune, India.
Protein J. 2024 Aug;43(4):858-868. doi: 10.1007/s10930-024-10218-9. Epub 2024 Jul 16.
Antimicrobial peptides have gradually gained advantages over small molecule inhibitors for their multifunctional effects, synthesising accessibility and target specificity. The current study aims to determine an antimicrobial peptide to inhibit PknB, a serine/threonine protein kinase (STPK), by binding efficiently at the helically oriented hinge region. A library of 5626 antimicrobial peptides from publicly available repositories has been prepared and categorised based on the length. Molecular docking using ADCP helped to find the multiple conformations of the subjected peptides. For each peptide served as input the tool outputs 100 poses of the subjected peptide. To maintain an efficient binding for relatively a longer duration, only those peptides were chosen which were seen to bind constantly to the active site of the receptor protein over all the poses observed. Each peptide had different number of constituent amino acid residues; the peptides were classified based on the length into five groups. In each group the peptide length incremented upto four residues from the initial length form. Five peptides were selected for Molecular Dynamic simulation in Gromacs based on higher binding affinity. Post-dynamic analysis and the frame comparison inferred that neither the shorter nor the longer peptide but an intermediate length of 15 mer peptide bound well to the receptor. Residual substitution to the selected peptides was performed to enhance the targeted interaction. The new complexes considered were further analysed using the Elastic Network Model (ENM) for the functional site's intrinsic dynamic movement to estimate the new peptide's role. The study sheds light on prospects that besides the length of peptides, the combination of constituent residues equally plays a pivotal role in peptide-based inhibitor generation. The study envisages the challenges of fine-tuned peptide recovery and the scope of Machine Learning (ML) and Deep Learning (DL) algorithm development. As the study was primarily meant for generation of therapeutics for Tuberculosis (TB), the peptide proposed by this study demands meticulous invitro analysis prior to clinical applications.
抗菌肽在多功能作用、合成可及性和靶标特异性方面逐渐优于小分子抑制剂。本研究旨在确定一种抗菌肽，通过有效地结合螺旋定向铰链区域来抑制丝氨酸/苏氨酸蛋白激酶（STPK）PknB。从公共存储库中准备了一个由 5626 种抗菌肽组成的文库，并根据长度进行了分类。使用 ADCP 的分子对接有助于找到所研究肽的多种构象。对于作为输入的每个肽，该工具输出该肽的 100 个构象。为了保持相对较长时间的有效结合，只选择那些在观察到的所有构象中始终与受体蛋白的活性位点结合的肽。每个肽都有不同数量的组成氨基酸残基；肽根据长度分为五组。在每组中，肽的长度从初始长度形式递增四个残基。基于更高的结合亲和力，在 Gromacs 中选择了五个肽进行分子动力学模拟。在动态分析和帧比较之后推断，不是较短的肽，也不是较长的肽，而是长度为 15 个残基的中间肽与受体结合良好。对选定的肽进行残基取代以增强靶向相互作用。进一步使用弹性网络模型（ENM）对新复合物进行分析，以评估新肽在功能位点固有动态运动中的作用。该研究表明，除了肽的长度外，组成残基的组合同样在基于肽的抑制剂生成中起着关键作用。该研究设想了微调肽回收的挑战以及机器学习（ML）和深度学习（DL）算法开发的范围。由于该研究主要是为结核病（TB）治疗生成药物，因此该研究提出的肽在临床应用之前需要进行细致的体外分析。
