Investigation of structure-activity relationships of ROCK inhibitor compounds using molecular modeling techniques and identification of estimated ROCK inhibitor compounds by virtual high-throughput screening method.
Project no. 29624 · Status: Kapanmış (Yayın bekleniyor) · 2023
Summary
<p>Rho-associated protein kinases (ROCKs) are members of the serine-threonine protein kinase family. Members of this family contribute to signaling pathways associated with cellular activities such as cell adhesion and migration, actin organization, and cytokinesis. ROCK enzymes consist of two isoforms, ROCK1 and ROCK2. Although these enzymes have similar functional domains and show significant amino acid similarity, they are localized in different regions and show different mechanism effects. ROCK1 is highly expressed in the lung, liver, spleen, kidney and testes, while ROCK2 is abundant in the brain and heart. The Rho/ROCK pathway has been reported to be involved in cardiovascular diseases, neurological diseases, immune system diseases and oncology. For this reason, it has been thought that inhibition of ROCKs may be useful in the treatment of related diseases, and the drugs used in treatment have been developed, albeit in small numbers. The limited information is about structure-activity relationships of inhibitors used in clinics, phase studies, or as references due to the lack of X-ray crystal structures or reported the complex with one isoform. However, due to the limited number of compounds targeting ROCK enzymes in treatment and the diversity of diseases caused by the ROCK pathway, new inhibitor compounds are needed. In our study, the structure-activity relationships of drugs and several important ROCK inhibitors were investigated using in silico molecular modeling techniques, and their potential target sites were determined. In addition, using virtual screening techniques, three potentially active lead compound candidates for each of the ROCK isoforms were identified and reported.</p>