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Research Unit of Prof. Fiorella Meneghetti  

Coordinator: Prof. Fiorella Meneghetti

Research Collaborators: Dr. Elena Pini, Dr. Matteo Mori (Dottorando di ricerca)

X-Ray Crystallographic Laboratory

The X-Ray Crystallographic Laboratory located at the Department of Pharmaceutical Sciences aims at understanding the structure, function and target interactions of important novel pharmaceutical derivatives at a molecular level. The methods employed cover a wide range of techniques useful for the identification and geometric characterization of the analyzed compounds. The X-Ray data are collected on diffractometers, available through scientific collaborations (small molecules), and/or at synchrotron beamlines (macromolecules). The laboratory is equipped for crystal growth optimization and protein crystallization screening techniques.
Three main areas of research:

  • Structural biology of enzymes
  • Structure-activity relationships of pharmaceutical molecules endowed with pharmaceutical interest
  • Crystallography of metal complexes

 

Current projects

1)    Structural investigation of new MbtI inhibitors

This research concerns the co-crystallization and structural resolution of new active compounds as Salicylate Synthase (MbtI) inhibitors. Iron absorption is a fundamental process for the pathogenicity of Mycobacterium tuberculosis (Mtb); iron acts as a co-factor in numerous essential biological processes, such as DNA biosynthesis and cellular respiration. In order to chelate non-heme iron, Mtb synthesizes siderophores, known as mycobactins and carboxymycobactins; in light of this, their biosynthesis has been identified as a potential target for the development of new antitubercular agents.

The implementation of this project aims at the design, synthesis, characterization and biological evaluation of inhibitors of MbtI, the enzyme that catalyzes the first step of the biosynthesis of these siderophores; the final objective is to reach the discovery of new potential drugs, active on bacteria-specific targets. The pharmacological tests are carried out at the University of Pavia.

The X-ray analysis of the complexes between the new potential drugs and the enzyme can provide data on the structural requirements important for obtaining selective molecules, producing fundamental information for pharmacological development processes (Collaborations: Dr. Stefania Villa, Dr. Arianna Gelain, Dr. Elena Pini, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano).

L. R. Chiarelli, M. Mori, G. Beretta, A. Gelain, E. Pini, J. C. Sammartino, G. Stelitano, D. Barlocco, L. Costantino, M. Lapillo, G. Poli, M. Bellinzoni, T. Tuccinardi, S. Villa and F. Meneghetti.
“New Insight into Structure-Activity of Furan-Based Salicylate Synthase (MbtI) Inhibitors as Potential Antitubercular Agents” - J. Enzyme Inhib. Med. Chem. 2019, 34, 823-828.

L. R. Chiarelli, M. Mori, D. Barlocco, G. Beretta, A. Gelain, E. Pini, M. Porcino, G. Mori, G. Stelitano, L. Costantino, M. Lapillo, D. Bonanni, G. Poli, T. Tuccinardi, S. Villa, F. Meneghetti.
“Discovery and Development of Novel Salicylate Synthase (MbtI) Furanic Inhibitors as Antitubercular Agents” - Eur. J. Med. Chem. 2018, 155, 754-763.

2) Structural studies on peptidomimetics and metallic complexes

This research focuses on the structural study of new peptidomimetics, in particular cyclic structures, conformationally constrained, able to act as reverse beta-turn mimetics. Their crystallographic structures are an important starting point for evaluating their ability to induce reverse turns in short bioactive peptides. The project aims to find efficient synthetic routes of new peptidomimetics having a specific biological target. The study of their conformational properties in the solid state is interesting, as this class of compounds is characterized by a high conformational freedom.

The structural analysis of coordination complexes between metals and the bispidinic nucleus is of great importance for understanding the structural modifications of the ligands following the coordination with the metal; this studies can provide useful structure-activity relationships in relation to the different substituents of the central scaffold. (Collaborations: Prof. Alessandra Silvani and Dr. Carlo Castellano, Dipartimento di Chimica, Università degli Studi di Milano, Prof. Alessandro Sacchetti, Prof. Alessandro Volonterio, Dipartimento di Chimica, Materiali ed Ingegneria Chimica "G. Natta", Politecnico di Milano).

M. C. Bellucci, M. Frigerio, C. Castellano, F. Meneghetti, A. Sacchetti, A. Volonterio.
“Design, Synthesis, and Conformational Analysis of 3-Cyclo-Butylcarbamoyl Hydantoins as Novel Hydrogen Bond Driven Universal Peptidomimetics” - Org. Biomol. Chem. 2018, 16, 521-525.

A. Rossetti, S. Landoni, F. Meneghetti,* C. Castellano, M. Mori, A. Sacchetti*.
“Application of chiral bi- and tetra-dentate bispidine-derived ligands in the Copper (II)-catalyzed asymmetric Henry reaction” - New J. Chem. 2018, 42, 12072-12081.

 

3) Structural characterization of polymorphic forms.

The subject of this topic is the structural analysis of compounds endowed with pharmaceutical / toxicological interest in order to develop solutions to optimize the control of the crystallization processes.
The X-ray characterization of polymorphs, or of aggregates of the same compound with different molecules (e.g. solvates), provides fundamental information for a rational choice of the most suitable solid form for the development of new drugs, in particular for what concerns the relevant implications in the patent field (Collaboration: Prof. Patrizia Ferraboschi, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano).

P. Ferraboschi, P. Ciuffreda, S. Ciceri, P. Grisenti, C. Castellano, F. Meneghetti*.
“Crystallographic and spectroscopic study on a known orally active progestin” - Steroids 2015, 104, 137-144.

Research topics:

X-Ray crystallography analysis of novel pharmaceutical derivatives and macromolecules.

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