类风湿性关节炎 (RA) 是一种慢性、对称性炎症性自身免疫性疾病，其特征是疼痛、肿胀的滑膜炎和关节糜烂，可导致骨和软骨损伤，并导致进行性残疾。尽管治疗选择有所增加，但一些患者仍然出现反应不足或无法忍受的不良反应。因此，RA 的治疗选择仍然相当有限。 AKT1 酶对于设计治疗各种人类疾病的药物至关重要，它支持正常细胞和恶性细胞的增殖、存活、代谢和血管生成等细胞功能。因此，AKT 丝氨酸/苏氨酸激酶 1 被认为对于旨在减轻 RA 机制的靶向治疗策略至关重要。在这种背景下，针对 AKT1 的研究代表了开发新型抗关节炎药物的创新方法。这项研究的主要目标是使用分子建模和动力学模拟 (MDS) 以及基于形状的虚拟筛选 (SBVS) 等计算技术来优先考虑 AKT1 抑制剂。通过筛选来自 ChemDiv 和 IMPPAT 数据库的化合物库，采用组合 SBVS 方法来预测 AKT1 的有效抑制剂。根据 SBVS 结果，仅对前三种化合物 ChemDiv_7266、ChemDiv_2796 和 ChemDiv_9468 进行了基于其高结合亲和力和有利的 ADME/Tox 特性的稳定性分析。 SBVS 的研究结果表明，关键残基（包括 Glu17、Gly37、Glu85 和 Arg273）对于排名最高的先导化合物在 AKT1 活性位点的成功结合有显着贡献。这一见解有助于了解这些先导化合物抑制 RA 的特异性结合机制，促进更有效治疗药物的合理设计。© 2024。作者，获得 Springer Nature Switzerland AG 的独家许可。

Rheumatoid Arthritis (RA) is a chronic, symmetrical inflammatory autoimmune disorder characterized by painful, swollen synovitis and joint erosions, which can cause damage to bone and cartilage and be associated with progressive disability. Despite expanded treatment options, some patients still experience inadequate response or intolerable adverse effects. Consequently, the treatment options for RA remain quite limited. The enzyme AKT1 is crucial in designing drugs for various human diseases, supporting cellular functions like proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. Therefore, AKT serine/threonine kinase 1 is considered crucial for targeting therapeutic strategies aimed at mitigating RA mechanisms. In this context, directing efforts toward AKT1 represents an innovative approach to developing new anti-arthritis medications. The primary objective of this research is to prioritize AKT1 inhibitors using computational techniques such as molecular modeling and dynamics simulation (MDS) and shape-based virtual screening (SBVS). A combined SBVS approach was employed to predict potent inhibitors against AKT1 by screening a pool of compounds sourced from the ChemDiv and IMPPAT databases. From the SBVS results, only the top three compounds, ChemDiv_7266, ChemDiv_2796, and ChemDiv_9468, were subjected to stability analysis based on their high binding affinity and favorable ADME/Tox properties. The SBVS findings have revealed that critical residues, including Glu17, Gly37, Glu85, and Arg273, significantly contribute to the successful binding of the highest-ranked lead compounds at the active site of AKT1. This insight helps to understand the specific binding mechanism of these leads in inhibiting RA, facilitating the rational design of more effective therapeutic agents.© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.