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Eur J Med Chem. 2016 Jun 30;116:36-45. doi: 10.1016/j.ejmech.2016.03.045. Epub 2016 Mar 19.

The chemosensitizing agent lubeluzole binds calmodulin and inhibits Ca(2+)/calmodulin-dependent kinase II.

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Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via E. Orabona 4, 70126 Bari, Italy.
Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via E. Orabona 4, 70126 Bari, Italy. Electronic address:
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II, 80131 Napoli, Italy.
Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari' Aldo Moro', via E. Orabona 4, 70126 Bari, Italy.
Dipartimento dell'Emergenza e dei Trapianti di Organi, Policlinico - P.zza Giulio Cesare, 70124 Bari, Italy.
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro (IRCCS SMIST), U.O.C. Terapia Immunologia, L.go R. Benzi, 10, 16132 Genova, Italy.


An affinity capillary electrophoresis (ACE) method to estimate apparent dissociation constants between bovine brain calmodulin (CaM) and non-peptidic ligands was developed. The method was validated reproducing the dissociation constants of a number of well-known CaM ligands. In particular, the potent antagonist 125-C9 was ad hoc synthesized through an improved synthetic procedure. The ACE method was successfully applied to verify CaM affinity for lubeluzole, a well-known neuroprotective agent recently proved useful to potentiate the activity of anti-cancer drugs. Lubeluzole was slightly less potent than 125-C9 (Kd = 2.9 ± 0.7 and 0.47 ± 0.06 μM, respectively) and displayed Ca(2+)/calmodulin-dependent kinase II (CaMKII) inhibition (IC50 = 40 ± 1 μM). Possible binding modes of lubeluzole to CaM were explored by docking studies based on the X-ray crystal structures of several trifluoperazine-CaM complexes. An estimated dissociation constant in good agreement with the experimental one was found and the main aminoacidic residues and interactions contributing to complex formation were highlighted. The possibility that interference with Ca(2+) pathways may contribute to the previously observed chemosensitizing effects of lubeluzole on human ovarian adenocarcinoma and lung carcinoma cells are discussed.


Affinity capillary electrophoresis; Anti-cancer activity; Calmodulin; Docking; Human carcinoma cells; Lubeluzole; Voltage-gated sodium channels

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