Research
Metal-catalyzed reactions mechanisms
​​​​
Metal-catalyzed reactions are fundamental in chemistry, enabling efficient transformations that would otherwise be challenging or unfeasible. Metal complex formation promotes bond activation, electron transfer, and molecular rearrangements, making metal-based catalysts indispensable in organic synthesis, industrial chemistry, and biochemistry.
Our research focuses on a detailed characterization of group 8 metal-catalyzed cyclotrimerizations, aiming for a rational catalyst design to enhance efficiency and selectivity. Additionally, we explore polymetallic catalysts and the role of cooperative effects in catalysis.
L. Orian, N. P. J. van Stralen, F. M. Bickelhaupt, Cyclotrimerization reactions catalyzed by Rh(I) half-sandwich complexes: a mechanistic Density Functional study Organometallics 26, 3816-3830 (2007).
​
L. Orian, L. P. Wolters, F.M. Bickelhaupt, In silico design of heteroaromatic half-sandwich Rh(I) catalysts for Acetylene [2+2+2] cyclotrimerization: Evidence of a reverse indenyl effect Chem. Eur. J. 19, 13337-13347 (2013). (with COVER)
M. Dalla Tiezza, F. M. Bickelhaupt, L. Orian Half-sandwich metal-catalyzed alkyne [2+2+2] cycloadditions and the slippage span model, Chem. Open, 8(2), 143-154 (2019). (with COVER)
​
L. Orian, M. Bickelhaupt Designing Rh(I) half-sandwich catalysts for alkyne [2+2+2] cycloadditions Synlett. 32, 561-572 (2021).
Enzymatic mechanisms
​
Understanding enzymatic mechanisms is crucial for comprehending biological processes and advancing drug development, biotechnology, and metabolic engineering.
Our research focuses on enzyme families such as glutathione, peroxidases and Cys-proteases, with a broader interest in proteins containing peroxidatic cysteines. We investigate their mechanisms by integrating classical atomistic simulations with high-accuracy quantum mechanical calculations, ultimately constructing molecular models of their catalytic sites.
​​
VIP PAPER M. Bortoli, M. Torsello, F. M. Bickelhaupt, L. Orian Role of the chalcogen (S, Se, Te) in the oxidation mechanism of the glutathione peroxidase active site ChemPhysChem, 18, 2990-2998 (2017). (with COVER)
​
M. Dalla Tiezza, F. M. Bickelhaupt, L. Flohé, M. Maiorino, F. Ursini, L. Orian, A dual attack on the peroxide bond. The common principle of peroxidatic cysteine or selenocysteine residues. Redox Biol. 34, 101540 (2020).
​
L. Flohé, S. Toppo, L. Orian The glutathione peroxidase family: discoveries and mechanism Free Rad. Biol. Med. 187, 113-122 (2022).
​
F. B. Omage, A. Madabeni, A. R. Tucci, P. A. Nogara, M. Bortoli, A. dos Santos Rosa, V. N. Ferreira, J. B. T. Rocha, M. Dias Miranda, L. Orian Diphenyl diselenide and SARS-CoV-2: in silico exploration of the mechanisms of inhibition of Main protease (Mpro) and Papain-like protease (PLpro) J. Chem. Inf. Mod. 63, 7, 2226-2239 (2023).
ROS scavenging mechanisms
​​Reactive Oxygen Species (ROS) are highly reactive oxygen-derived molecules that play crucial roles in cellular signaling and immune responses. However, excessive ROS levels can induce oxidative stress, leading to cellular damage and contributing to aging, cancer, and neurodegenerative diseases. To maintain redox balance and prevent oxidative damage, cells have developed a complex network of enzymatic and non-enzymatic ROS scavengers. Disruptions in these protective mechanisms are linked to oxidative stress-related diseases, highlighting antioxidant therapy as a promising approach for prevention and treatment.
Our research focuses on uncovering the fundamental mechanisms of ROS scavenging and establishing structure-activity relationships inspired by natural compounds and psychotropic drugs. We integrate high-accuracy quantum mechanical calculations with machine learning protocols to advance this understanding.
M. Bortoli, M. Dalla Tiezza, C. Muraro, C. Pavan. G. Ribaudo, A. Rodighiero, C. Tubaro, G. Zagotto, L. Orian Psychiatric Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed in silico Comp. Struct. Biotech. J., 17, 311-318 (2019).
C. Muraro, M. Polato, M. Bortoli, F. Aiolli, L. Orian Machine learning assisted study of the radical scavenging activity of biologically relevant compounds and drugs J. Chem. Phys. 153, 114117 (2020).
​
G. Ribaudo, M. Bortoli, C. Pavan, G. Zagotto, L. Orian Antioxidant potential of psychotropic drugs: from clinical evidence to in vitro and in vivo assessment and toward a new challenge for in silico molecular design Antioxidants 9, 714 (2020).
​
D. Zeppilli, G. Grolla, V. Di Marco, G. Ribaudo, L. Orian Radical Scavenging and Anti-Ferroptotic Molecular Mechanism of Olanzapine: Insight from a Computational Analysis Inorg. Chem. 63, 21856-21867 (2024) (with COVER)
Organic oxidation reactions mechanisms
​​​Hydrogen peroxide (H₂O₂) is a key oxidant in both chemistry and biology, playing a crucial role in oxidation reactions. In chemical synthesis, H₂O₂ is widely used as a green oxidant due to its high atom economy and benign byproducts, typically generating only water. It participates in selective oxidations, epoxidations, and hydroxylations, often catalyzed by transition metals or enzymes.
In biological systems, Hâ‚‚Oâ‚‚ serves as a signaling molecule and a key intermediate in oxidative metabolism. It is produced by various enzymatic pathways, such as superoxide dismutase activity on superoxide radicals. However, its accumulation can lead to oxidative stress, damaging biomolecules like DNA, proteins, and lipids. Cells regulate Hâ‚‚Oâ‚‚ levels through antioxidant enzymes such as catalase, peroxiredoxins, and glutathione peroxidases, which decompose it into water and oxygen to maintain redox balance.
We investigate the detailed mechanism of oxidation of different substrates mediated by selenium and its chalcogen siblings, pinpointing the role of these catalysts in organic synthesis and in biology. Our models are developed using accurate quantum mechanical calculations combined to activation strain analysis and molecular orbital theory.
G. Ribaudo, M. Bellanda, I. Menegazzo, L. P. Wolters, M. Bortoli, G. Ferrer-Sueta, G. Zagotto, L. Orian Mechanistic insight into the oxidation of organic phenylselenides by H2O2 Chem. Eur. J., 23, 2405-2422 (2017).
L. Orian, L. Flohé Selenium catalyzed reduction of hydroperoxides in chemistry and biology Antioxidants, 10, 1560 (2021).
​
D. Zeppilli, A. Madabeni, L. Sancineto, L. Bagnoli, C. Santi, L. Orian Role of Group 12 metals in the reduction of H2O2 by Santi's reagent: a computational mechanistic investigation Inorg. Chem. 62(42), 17288-17298 (2023) (with COVER)
A. Madabeni, D. Tanini, A. Capperucci, L. Orian Untangling the catalytic importance of Se oxidation state in organoselenium-mediated oxygen-transfer reactions: the conversion of aniline to nitrobenzene Chem. Science 15, 12126–12137 (2024)