Naskar Avigyan, Bhanja Kousik K, Roy Rakesh K, Patra Niladri
Department of Chemistry and Chemical Biology, Indian Institute of Technology (ISM) Dhanbad, Dhanbad, India.
J Biomol Struct Dyn. 2024;42(19):10129-10149. doi: 10.1080/07391102.2023.2255675. Epub 2023 Sep 13.
More than 40 mutations in the multidomain leucine-rich repeat kinase 2 (LRRK2) are found and mutation G2019S in the kinase domain is the most concerned with Parkinson's disease (PD). The discovery of the various types of inhibitors has largely emerged recently. However, the comparative study on molecular insight in WT and G2019S LRRK2 kinase domain upon binding of the inhibitors has not yet been explored in detail. This work considered five ATP-competitive Type I inhibitors complexed with WT and mutated LRRK2 kinase. Three reported potent and brain-penetrant inhibitors, GNE-7915, PF-06447475 and MLi-2 (comp1, comp2 and comp3 respectively) and also, another two inhibitors, Pyrrolo[2,3-b] pyridine derivative (comp4) and Pyrrolo[2,3-d] pyrimidine derivative (comp5), were used. In this work, classical and accelerated molecular dynamics (cMD and aMD) simulations were performed for a total of 12 systems (apo and holo). This study found structural and thermodynamic stability for all the inhibitors. Comparatively larger molecules (size 15.3 - 15.4 Å), comp1, comp3 and comp5, showed more selectivity towards mutated LRRK2 kinase in terms of flexibility of residues, compactness and dynamics of kinase, the stability inside the binding-pocket. Also, inhibitors comp3 and comp5 showed higher binding affinity towards G2019S LRRK2 among the five. Residues, E1948 and A1950 (in hinge region) were observed mainly to form hydrogen bonds with inhibitors. Finally, MLi-2 showed a conformational rearrangement by dihedral flipping in both WT and mutated systems but got stability in G2019S LRRK2. This work could potentially help design more improved and effective Type I inhibitors for G2019S LRRK2 kinase.
在多结构域富含亮氨酸重复激酶2（LRRK2）中发现了40多种突变，其中激酶结构域中的G2019S突变与帕金森病（PD）最为相关。近年来，各种类型的抑制剂大量涌现。然而，关于抑制剂结合后野生型和G2019S LRRK2激酶结构域的分子洞察的比较研究尚未得到详细探讨。这项工作研究了与野生型和突变型LRRK2激酶复合的五种ATP竞争性I型抑制剂。使用了三种已报道的强效且具有脑渗透性的抑制剂，即GNE-7915、PF-06447475和MLi-2（分别为化合物1、化合物2和化合物3），以及另外两种抑制剂，吡咯并[2,3-b]吡啶衍生物（化合物4）和吡咯并[2,3-d]嘧啶衍生物（化合物5）。在这项工作中，对总共12个系统（无配体和结合配体）进行了经典和加速分子动力学（cMD和aMD）模拟。该研究发现了所有抑制剂的结构和热力学稳定性。相对较大的分子（尺寸为15.3 - 15.4 Å），即化合物1、化合物3和化合物5，在残基灵活性、激酶紧凑性和动力学以及结合口袋内的稳定性方面，对突变型LRRK2激酶表现出更高的选择性。此外，在这五种抑制剂中，化合物3和化合物5对G2019S LRRK2表现出更高的结合亲和力。观察到残基E1948和A1950（在铰链区）主要与抑制剂形成氢键。最后，MLi-2在野生型和突变型系统中均通过二面角翻转发生构象重排，但在G2019S LRRK2中获得了稳定性。这项工作可能有助于设计出针对G2019S LRRK2激酶的更优化、更有效的I型抑制剂。
