一种用于识别治疗类风湿性关节炎（RA）的蛋白酶3（PAD4）抑制剂的多方面计算方法。

A Multifaceted Computational Approach to Identify PAD4 Inhibitors for the Treatment of Rheumatoid Arthritis (RA).

作者信息

Alturki Mansour S, Gomaa Mohamed S, Tawfeeq Nada, Al Khzem Abdulaziz H, Shaik Mohsina B, Alshaikh Jafar Murtadha, Alsamen Mohammad, Al Nahab Hasan, Al-Eid Mohammad, Almutawah Alhassan, Rants'o Thankhoe A, Ayil Khaled A G, Almaghrabi Mohammed

机构信息

Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.

College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.

出版信息

Metabolites. 2025 Feb 25;15(3):156. doi: 10.3390/metabo15030156.

DOI:10.3390/metabo15030156

PMID:40137121

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11943705/

Abstract

BACKGROUND/OBJECTIVES: Neutrophil cells' lysis forms the extracellular traps (NETs) to counter the foreign body during insults to the body. Peptidyl arginine deiminase (PAD) participates in this process and is then released into the extracellular fluid with the lysed cell components. In some diseases, patients with abnormal function of PADs, especially PAD 4, tend to form autoantibodies against the abnormal citrullinated proteins that are the result of PAD activity on arginine side chains. Those antibodies, which are highly distinct in RA, are distinctly anti-citrullinated protein antibodies (ACPA). This study used an in-silico drug repurposing approach of FDA-approved medications to identify potential alternative medications that can inhibit this process and address solutions to the current limitations of existing therapies.

METHODS

We utilized Maestro Schrödinger as a computational tool for preparing and docking simulations on the PAD 4 enzyme crystal structure that is retrieved from RCSB Protein Data Bank (PDB ID: 4X8G) while the docked FDA-approved medications are obtained from the Zinc 15 database. The protein was bound to GSK 199-an investigational compound-as a positive control for the docked molecules. Preparation of the protein was performed by Schrödinger Protein Preparation Wizard tool. Binding pocket determination was performed by Glide software (Schrödinger Release 2021-3:Schrödinger, LLC., New York, NY, USA, 2021). and validation of molecular docking was carried out through the redocking of GSK 199 and superimposition. After that, standard and induced fit docking were performed.

RESULTS/CONCLUSIONS: Among the four obtained hits Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol, which showed the highest XP scores providing favorable binding interactions. The induced-fit docking (IFD) results displayed the strong binding affinities of Ioversol, Pemetrexed, Leucovorin, Chlordiazepoxide in the order IFD values -11.617, -10.599, -10.521, -9.988, respectively. This research investigates Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol as potential repurposing agents in the treatment of rheumatoid arthritis (RA) as they are identified as PAD4 inhibitors.

摘要

背景/目的：中性粒细胞裂解形成细胞外陷阱（NETs）以应对机体受到侵害时的异物。肽基精氨酸脱氨酶（PAD）参与此过程，随后与裂解的细胞成分一起释放到细胞外液中。在某些疾病中，PADs功能异常的患者，尤其是PAD 4，倾向于形成针对异常瓜氨酸化蛋白的自身抗体，这些蛋白是PAD对精氨酸侧链作用的结果。在类风湿性关节炎（RA）中，这些抗体高度特异，即明显的抗瓜氨酸化蛋白抗体（ACPA）。本研究采用美国食品药品监督管理局（FDA）批准药物的计算机药物重新利用方法，以识别能够抑制此过程的潜在替代药物，并解决现有疗法当前局限性的解决方案。

方法

我们利用Maestro Schrödinger作为计算工具，对从RCSB蛋白质数据库（PDB ID：4X8G）检索到的PAD 4酶晶体结构进行制备和对接模拟，而对接的FDA批准药物则从锌15数据库获得。该蛋白质与GSK 199（一种研究性化合物）结合作为对接分子的阳性对照。蛋白质的制备由Schrödinger蛋白质制备向导工具完成。结合口袋的确定由Glide软件（Schrödinger Release 2021-3：Schrödinger，LLC.，纽约，美国，2021）进行。分子对接的验证通过GSK 199的重新对接和叠加进行。之后，进行标准对接和诱导契合对接。

结果/结论：在获得的四个命中物培美曲塞、亚叶酸钙、氯氮卓和碘海醇中，它们显示出最高的XP分数，提供了良好的结合相互作用。诱导契合对接（IFD）结果显示，碘海醇、培美曲塞、亚叶酸钙、氯氮卓的结合亲和力较强，IFD值分别为-11.617、-10.599、-10.521、-9.988。本研究调查了培美曲塞、亚叶酸钙、氯氮卓和碘海醇作为类风湿性关节炎（RA）治疗中潜在的重新利用药物，因为它们被确定为PAD4抑制剂。