New Insights into the LANCL2-<b>ABA</b> Binding Mode towards the Evaluation of New LANCL Agonists
Naomi Scarano,
Francesco Di Palma,
Nicola Origlia,
Francesca Musumeci,
Silvia Schenone,
Sonia Spinelli,
Mario Passalacqua,
Elena Zocchi,
Laura Sturla,
Elena Cichero,
Andrea Cavalli
Affiliations
Naomi Scarano
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genova, Viale Benedetto XV, 3, 16132 Genoa, Italy
Francesco Di Palma
Computational & Chemical Biology, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
Nicola Origlia
National Research Council (CNR), Institute of Neuroscience, 56124 Pisa, Italy
Francesca Musumeci
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genova, Viale Benedetto XV, 3, 16132 Genoa, Italy
Silvia Schenone
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genova, Viale Benedetto XV, 3, 16132 Genoa, Italy
Sonia Spinelli
Laboratorio di Nefrologia Molecolare, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy
Mario Passalacqua
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genova, Italy
Elena Zocchi
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genova, Italy
Laura Sturla
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genova, Italy
Elena Cichero
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genova, Viale Benedetto XV, 3, 16132 Genoa, Italy
Andrea Cavalli
Computational & Chemical Biology, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
The lanthionine synthetase C-like (LANCL) proteins include LANCL2, which is expressed in the central nervous system (CNS) and in peripheral tissues. LANCL2 exhibits glutathionylation activity and is involved in the neutralization of reactive electrophiles. Several studies explored LANCL2 activation as a validated pharmacological target for diabetes and inflammatory bowel disease. In this context, LANCL2 was found to bind the natural product abscisic acid (ABA), whose pre-clinical effectiveness in different inflammatory diseases was reported in the literature. More recently, LANCL2 attracted more attention as a valuable resource in the field of neurodegenerative disorders. ABA was found to regulate neuro-inflammation and synaptic plasticity to enhance learning and memory, exhibiting promising neuroprotective effects. Up until now, a limited number of LANCL2 ligands are known; among them, BT-11 is the only compound patented and investigated for its anti-inflammatory properties. To guide the design of novel putative LANCL2 agonists, a computational study including molecular docking and long molecular dynamic (MD) simulations of both ABA and BT-11 was carried out. The results pointed out the main LANCL2 ligand chemical features towards the following virtual screening of a novel putative LANCL2 agonist (AR-42). Biochemical assays on rat H9c2 cardiomyocytes showed a similar, LANCL2-mediated stimulation by BT-11 and by AR-42 of the mitochondrial proton gradient and of the transcriptional activation of the AMPK/PGC-1α/Sirt1 axis, the master regulator of mitochondrial function, effects that are previously observed with ABA. These results may allow the development of LANCL2 agonists for the treatment of mitochondrial dysfunction, a common feature of chronic and degenerative diseases.
