Theoretical models of staurosporine and analogs uncover detailed structural information in biological solution

• Published in: Journal of molecular graphics & modelling Vol. 126; p. 108653
• Main Authors: Fontana, Crisciele, de Meirelles, João Luiz, Verli, Hugo
• Format: Journal Article
• Language: English
• Published: United States 01.01.2024
• Subjects: Ligands; Models, Theoretical; Molecular Conformation; Molecular Dynamics Simulation; Staurosporine - pharmacology; Thermodynamics; Water - chemistry; Intermolecular interaction; Molecular dynamics; Water shell; Parameterization; Indolocarbazole; Conformation
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2023.108653

Staurosporine and its analogs (STA-analogs) are indolocarbazoles (ICZs) compounds able to inhibit kinase proteins in a non-specific way, while present antimicrobial and cytostatic properties. The knowledge of molecular features associated to the complexation, including the ligand shape in solution and thermodynamics of complexation, is substantial to the development of new bioactive ICZs with improved therapeutic properties. In this context, the empirical approach of GROMOS force field is able to accurately reproduce condensed phase physicochemical properties of molecular systems after parameterization. Hence, through parameterization under GROMOS force field and molecular simulations, we assessed STA-analogs dynamics in aqueous solution, as well as its interaction with water to probe conformational and structural features involved in complexation to therapeutic targets. The coexistence of multiple conformers observed in simulations, and confirmed by metadynamics calculations, expanding the conformational space knowledge of these ligands with potential implications in understanding the ligand conformational selection during complexation. Also, changes in availability to H-bonding concerning the different substituents and water can reflect on effects at complexation free energy due to variation at the desolvation energetic costs. Based on these results, we expect the obtained structural data provide systemic framework for rational chemical modification of STA-analogs.