Project Title: A combined theoretical and experimental approach to the rational design of high value chemicals with implications for biotherapeutic engineering. 

REFERENCE: (REF. CIPROM/2021/079) 
Funding Agencies: Generalitat Valenciana - European Regional Development Fund

SUMMARY: This research project is ultimately aimed at the design of new chemicals with tailored biotherapeutic applications. By combining experimental and computational approaches, we will focus on two main targets: the design and synthesis of SARS CoV-2 antiviral and anti-cancer drugs, metallosupramolecular complexes (from now on hosts) with biomedical applications. These metallosupramolecular hosts will be used both as direct anticancer agents, by means of the generation of singlet oxygen (1O2) for photodynamic therapy (PDT), and as drug delivery/release vectors of other anticancer drugs. Both, theoretical and experimental approaches to the target compounds will be performed by highly skilled researchers with years of experience in their respective fields of research. After the design and synthesis of the compounds, the final stage of the proposal will be the in-vivo testing of the newly designed abiotic enzyme inhibitors in replicas of the virus responsible of the COVID-19 pandemic, while the metallosupramolecular hosts will be tested in photodynamic destruction of cancer cells and as drug release/delivery vectors. Thus, this proposal transcends the traditional divisional boundaries of science and represents a highly interdisciplinary field of research. The development of this proposal should allow taking a step forward in applied medicinal chemistry.


RESEARCH GROUPS INVOLVED:

The Computational Biochemistry group (BioComp) :
https://www.biocomp.uji.es/home.html
The Organometallic and Homogeneous Catalysis group (QOMCAT) :
http://www.inam.uji.es/research-groups/rg2-organometallic-chemistry-and-homogeneous-catalysis
The Medium Effects Research group (MER) :
https://www.uv.es/efme/
The Organic and Medicinal Chemistry Group (OMC):  https://www.uji.es/serveis/ocit/base/grupsinvestigacio/detall?codi=164




LIST OF PUBLICATIONS: 

[1] K. Świderek, S. Velasco-Lozano, M. À. Galmés, I. Olazabal, H. Sardon, F. López-Gallego, V. Moliner "Mechanistic studies of a lipase unveil effect of pH on hydrolysis products of small PET modules" Nat. Commun. 14:3556. (2023) doi: 10.1038/s41467-023-39201-1

[2] A. Fernández-de-la-Pradilla, S. Royo, T. Schirmeister, F. Barthels, K. Świderek, F. V. González, V. Moliner "Impact of the Warhead of Dipeptidyl Keto Michael Acceptors on the Inhibition Mechanism of Cysteine Protease Cathepsin L"
ACS Catal. 13, 13354-13368 (2023) doi:10.1021/acscatal.3c02748

[3] K Arafet, S Royo, T Schirmeister, F Barthels, FV González, V Moliner "Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L"
ACS Catal. 13, 6289-6300 (2023). https://doi.org/10.1021/acscatal.3c01035

[4] S. Movilla, S. Martí, M. Roca, V. Moliner. Computational Study of the Inhibition of RgpB Gingipain, a Promising Target for the Treatment of Alzheimer’s Disease.
J. Chem. Inf. Model. 63, 3, 950–958 (2023), DOI: 10.1021/acs.jcim.2c01198.

[5] P. Gomez de Santos, A. González-Benjumea, A. Fernandez-Garcia, C. Aranda, Y. Wu, A. But, P. Molina-Espeja, D. Mate Maté, D. Gonzalez-Perez, W. Zhang, J. Kiebist, K. Scheibner, M. Hofrichter, K. Świderek, V. Moliner, J. Sanz-Aparicio, F. Hollmann, A. Gutiérrez, M. Alcalde. Engineering a Highly Regioselective Fungal Peroxygenase for the Synthesis of Hydroxy Fatty Acids. Just accepted in
Angew. Chemie Int. Ed. (2023), DOI: 10.1002/anie.202217372.

[6] K Arafet, L Scalvini, F Galvani, S Martí, V Moliner, M Mor, A Lodola "Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents"
J. Chem. Inf. Mod. (2023) 63, 1301-1312. https://doi.org/10.1021/acs.jcim.2c01586

[7] S. Ibañez, K. Swiderek, E. Peris, Unlocking a (pseudo)‐Mechanically Interlocked Molecule with a Coronene “Shoehorn.
Angew. Chem. Int. Ed. 2023, 62, e202301914. https://doi.org/10.1002/anie.202301914

[8] C. A. Ramos-Guzmán, J. J. Ruiz-Pernía, K. Zinovjev, I. Tuñón. Unveiling the Mechanistic Singularities of Caspases: A Computational Analysis of the Reaction Mechanism in Human Caspase‐1.
ACS Catal. 2023, 13, 4348−4361. https://doi.org/10.1021/acscatal.3c00037

[9] M. Andjelkovic, K. Zinovjev, C.A. Ramos-Guzmán, J. J. Ruiz- Pernía, I. Tuñón. Elucidation of the Active Form and Reaction Mechanism in Human Asparaginase Type III Using Multiscale Simulations.
J. Chem. Inf. Model. 2023, 63, 5676−5688. https://doi.org/10.1021/acs.jcim.3c00900

[10] C. A. Ramos-Guzman, M. Andjelkovic, K. Zinovjev, J. J. Ruiz-Pernía. I Tuñón. The impact of SARS-CoV-2 3CL protease mutations on nirmatrelvir inhibitory efficiency. Computational insights into potential resistance mechanisms.
Chem. Sci. 2023, 14, 2686. DOI: 10.1039/d2sc06584c