ИСТИНА

1. Objectives Mitophagy, the selective degradation of defective mitochondria, plays a crucial role in maintaining cellular homeostasis. Disruptions in this process can result in chronic inflammation, contributing to the development of various diseases such as atherosclerosis and cardiometabolic syndrome. Our study aims to identify potential activators of mitophagy, with the goal of developing novel anti-inflammatory therapeutics. By targeting mitophagy pathways, we seek to mitigate the inflammatory responses associated with non-infectious diseases. 2. Materials and methods An original python program was written to search for compounds in chemical databases. Molecular dynamics methods in the Schrödinger Biologics Suite and Schrödinger Maestro software packages were for evaluating mitophagy stimulating activity. The selection of discovered organic molecules was synthesized by a third-party laboratory using the Wittig reaction. 3. Results We developed a custom Python program to search for compounds with a known ability to stimulate mitophagy. 100 compounds with four types of biological activity were selected as a result of this script launch, i.e. PINK1 protein kinase activators (artificial cytokinin-like plant hormone kinetin and its analogues), sirtuin-3 activators (compound ADTL-SA1215), deubiquitation inhibitors (compounds MF-094 and MF-095), as well as compounds that alter the membrane potential of mitochondrial membranes (Jatrophone and Jatrogossone A). Then we obtained conformational characteristics of the most active stimulators of mitophagy by conducting simulations of molecular dynamics. Based on these data, 30 molecules with the best predicted mitophagy-stimulating activity were selected for in vitro tests. The organic synthesis of these compounds was carried out by conducting the Wittig reaction between maleinimide and aromatic aldehydes of various structures. The obtained benzylidene succinimides were used to produce diazo compounds for their subsequent modification with various heterocycles functionalized with hydroxyl groups. 4. Conclusion Our study identified and synthesized potential mitophagy activators for developing anti-inflammatory therapeutics for non-infectious diseases. Molecular dynamics simulations refined the selection to 30 candidates with predicted efficacy. However, in vitro experiments are still required to test these potential mitophagy stimulators, which could lead to the preclinical phase of drug development.