Mechanisms Contributing to Acquired Activated Protein C Resistance in Patients Treated with Thalidomide: A Molecular Dynamics Study.

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Contributed Indexing: Keywords: Multiple myeloma; molecular docking; resistance to activated protein C; serine protease; thalidomide; venous thromboembolism
Substance Nomenclature: 4Z8R6ORS6L (Thalidomide)
EC 3.4.- (Peptide Hydrolases)
Entry Date(s): Date Created: 20230125 Date Completed: 20230308 Latest Revision: 20230319
Update Code: 20240829
DOI: 10.2174/1871529X23666230123121602
PMID: 36694314
Autor: Maximiliano CL; Homeostasis and Thrombosis Clinic, Centro Medico Nacional 'La Raza', Instituto Mexicano del Seguro Social, Mexico City, Mexico.; Environmental Toxicology Laboratory, Instituto Politécnico Nacional, Mexico City, Mexico., Jaime GC; Homeostasis and Thrombosis Clinic, Centro Medico Nacional 'La Raza', Instituto Mexicano del Seguro Social, Mexico City, Mexico., Armando VL; Environmental Toxicology Laboratory, Instituto Politécnico Nacional, Mexico City, Mexico., Vega IL; Environmental Toxicology Laboratory, Instituto Politécnico Nacional, Mexico City, Mexico., Victoria HG; Environmental Toxicology Laboratory, Instituto Politécnico Nacional, Mexico City, Mexico., Erika MH; Homeostasis and Thrombosis Clinic, Centro Medico Nacional 'La Raza', Instituto Mexicano del Seguro Social, Mexico City, Mexico.
Jazyk: angličtina
Zdroj: Cardiovascular & hematological disorders drug targets [Cardiovasc Hematol Disord Drug Targets] 2023; Vol. 22 (4), pp. 237-244.
DOI: 10.2174/1871529X23666230123121602
Abstrakt: Introduction: There is a high incidence of venous thromboembolism (VTE) in patients with Multiple Myeloma (MM), however; until now, the exact mechanisms behind VTE in MM are unknown, and some of the elements that may play a significant role are the treatment with an immunomodulator (IMiD) and acquired resistance to activated protein C (APC).
Objective: The study aims to reveal the possible mechanisms linked to the reduced antithrombotic activity of APC associated with thalidomide.
Methods: The molecular docking approach was used to ascertain the in silico inhibitory potential of thalidomide on the APC protease domain in the architecture of the catalytic triad and its interaction with major substrate binding sites.
Results: The coupling showed that the inhibitory activity of thalidomide depends on the induction of structural changes in the protease domain of APC, at the level of the Ser/His/Asp catalytic triad, as a result of a significant increase between the distances of CαAsp102 and Cα Ser195 (11.175 angstroms, increase 14.83%) and between CαSer195 and CαHis57 (9.478 angstroms, increase 13.78 %). This can result in an inefficient transfer of the proton between these residues, the other possible mechanism of inhibition, is a potential reduced binding of the substrate as a result of a direct interaction through a carbon-hydrogen bond on His57, an H-bond on Arg306, and a carbon hydrogen bond on Arg506.
Conclusion: We demonstrate the in silico inhibitory potential of thalidomide on APC, through two possible inhibition mechanisms, a pathophysiologically relevant finding to understand the factors that can affect the stability and functions of APC in vivo.
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Databáze: MEDLINE
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