Data di Pubblicazione:
2022
Citazione:
Identification of novel potential B4GALT6 inhibitors through a large scale virtual screening / C. Papotto, E. Sabato, D. Lecca, C. Matera, M. DE AMICI, A. Pedretti, C.M.L. Dallanoce, G. Vistoli. ((Intervento presentato al 21. convegno Merck Young Chemists' Symposium : November, 21 - 23 tenutosi a Rimini nel 2022.
Abstract:
Recently, the crucial role of the glycolipid Lactosylceramide (LacCer) has been
outlined in the evolution of the progressive form (PMS) of Multiple Sclerosis (MS).
LacCer is synthetized by the enzyme B4GALT6, a galactosyl transferase expressed
exclusively by reactive astrocytes, and acts in an autocrine manner, driving further
inflammation and promoting neurodegeneration. The blockage of B4GALT6 caused a
halt to the progression of the disease in established models of MS [1]. Despite these
promising results, to date no selective inhibitors acting on this enzyme have been
developed.
On these grounds, a virtual screening study on B4GALT6 was carried out with the
aim of finding novel inhibitors through the screening of an extended dataset of
purchasable compounds. Since an experimental structure of the enzyme is not
available, two models were generated through a homology modelling approach,
mimicking two important conformational states of the enzyme. Then, a docking protocol
was developed and optimized, using a purposely collected database including
presumed B4GALT6 inhibitors. This protocol was based on the binding space concept
and employed an enrichment factor optimization algorithm to create consensus models
[2]. These models were then utilized to virtually screen the SPECS screening
database, composed of over 207.000 molecules. Based on the computational results,
the most promising candidates were further studied to characterize the interaction with
the target, assessing the potential inhibition properties
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Keywords:
Multiple Sclerosis; Progressive Multiple Sclerosis; MS; Virtual Screening; Lactosylceramide;
Elenco autori:
C. Papotto, E. Sabato, D. Lecca, C. Matera, M. DE AMICI, A. Pedretti, C.M.L. Dallanoce, G. Vistoli
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