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HIT-TO-LEAD OPTIMIZATION

  • We routinely apply high throughput virtual screening campaigns to identify hit compounds. We contributed to develop FLAP, a software designed to perform ligand-based, structure-based and pharmacophore based screenings as well as docking. Recent FLAP applications include the discovery of hit compounds with antiviral efficacy against SARS-CoV-2 and influenza virus, the discovery of inhibitors and substrates for a novel proton antiporter, choline-kinase inhibitors, among the others. FLAP was also used to generate pharmacophoric and toxicophoric models to inspire hit-to-lead optimization.

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Goracci L, Nurisso A, Roussel E, Pérès B, Chaptal V, Falson P, Marminon C, Jose J, Le Borgne M, Boumendjel A. Inhibitors of ABCG2-mediated multidrug resistance: Lead generation through computer-aided drug design. Eur J Med Chem, 2023, 248, 115070.
Luque-Navarro PM, Carrasco-Jiménez MP, Goracci L, Paredes JM, Espinar-Barranco L, Valverde-Pozo J, Torretta A, Parisini E, Mariotto E, Marchioro C, Laso A, Marco C, Viola G, Lanari D, López Cara LC. New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action. Eur J Med Chem, 2023, 246,115003.

Mercorelli  B, Desantis  J, Celegato  M, Bazzacco  A, Siragusa  L, Benedetti  P, Eleuteri  M, Croci  F, Cruciani  F, Goracci  L, Loregian  A. Discovery of novel SARS-CoV-2 inhibitors targeting the main protease Mpro by virtual screenings and hit optimization. Antiviral Res, 2022, 204, 105350.

Smirnova M, Goracci L, Cruciani G, Federici L, Declèves X, Chapy H, Cisternino S. Pharmacophore‐Based Discovery of Substrates of a Novel Drug/Proton‐Antiporter in the Human Brain Endothelial hCMEC/D3 Cell Line, Pharmaceutics, 2022, 14 (2), 255.

Lepri S, Buonerba F, Goracci L, Velilla I, Ruzziconi R, Schindler BD, Seo SM, Kaatz GW, Cruciani G. Indole based weapons to fight antibiotic resistance: a structure-activity relationship study. J Med Chem 2016, 59(3), 867-891.
Goracci L, Deschamps N, Randazzo GM, Petit C, Passos CD, Carrupt PA, Simoes-Pires C, Nurisso A. A rational approach for the identification of non-hydroxamate hdac6-selective inhibitors. Scientific Reports 2016, 6.

Muratore G, Goracci L, Mercorelli B, Foeglein A, Digard P, Cruciani G, Palù G, Loregian A. Small molecule inhibitors of influenza A and B viruses that act by disrupting subunit interactions of the viral polymerase. PNAS 2012, 109(16), 6247-6252.
 

  • We also combine in silico and experimental approaches to derive (Q)SAR. Among the most recent applications,  we generated experimentally driven rules to predict soft-spots of PROTAC based on phase I metabolism data, and methods to predict the risk for phospholipidosis induction.

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Goracci L, Desantis J, Valeri A, Castellani B, Eleuteri M, Cruciani G. Understanding the Metabolism of Proteolysis Targeting Chimeras (PROTACs): The Next Step toward Pharmaceutical Applications, J Med Chem, 2020, 63, 11615-11638.

Desantis J, Mammoli A, Eleuteri M, Coletti A, Croci F, Macchiarulo A, Goracci L. PROTACs bearing piperazine-containing linkers: what effect on their protonation state? RSC Adv.ances, 2022, 12, 21968.

Goracci L, Ceccarelli M, Bonelli D, Cruciani G. Modeling phospholipidosis induction: reliability and warnings. J Chem Inf  Model, 2013, 53(6), 1436-1446.

Goracci L, Buratta S, Urbanelli L, Ferrara G, Di Guida R, Emiliani C, Cross S. Evaluating the risk of phospholipidosis using a new multidisciplinary pipeline approach. Eur J Med Chem, 2015, 92, 49-63.

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