Welcome to our website!
- From enzymatic function to drug discovery -
- From enzymatic function to drug discovery -
We are a research group focused on the understanding of function and inhibition of pharmaceutically relevant enzymes and functionalized nanoparticles. Within the group, we develop and apply computational methods for multiscale molecular modeling and simulations, which are fully integrated with medicinal chemistry and structural/molecular biology. This multidisciplinary approach allows to design, synthesize and test promising compounds potentially endowed with the desired pharmacological effect to treat primarily cancer, neurological disorders and inflammatory-related diseases.
Enjoy your visit - and thanks for your interest !
Marco De Vivo & the group
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Dr. Marco De Vivo
Research Lab Director Molecular Modeling & Drug Discovery Lab Istituto Italiano di Tecnologia Via Morego, 30 - Genoa (16163), Italy Phone: +39 010 2897 404 Email: marco.devivo @ iit.it AWARDS, HONORS AND RECOGNITIONS - 2020: Director of the CECAM-IT-SIMUL Node - 2019: Associate Editor of JCTC (ACS Pub) - 2019: Advisory Board Member of Chem (Cell Press) - 2019: Editorial Advisory Board Member of JCIM (ACS Pub) - 2019: International Meetings Liaison ACS COMP division - 2018: Habilitation as Full Professor in Med Chem, Italy. - 2018: Member of the Scientific Committee for Associazione Italiana per la Ricerca sul Cancro (AIRC) - The Italian Association for Cancer Research - 2017: Outstanding Junior Faculty Award, ACS COMP Division - 2017: Scientific Advisory Board Member of BiKi Technologies - 2014: Habilitation as Associate Professor in Med Chem, Italy. - 2013: My First AIRC Grant (MFAG); talented Italian < 40 yo, for cancer research - 2006: O1 Visa – Issued by the United States Immigration Office for demonstrated extraordinary ability in the field of science. - 2003: Marco Polo Fellowship for excellent research projects funded by Uni. Bologna, Italy |
Our openings:
-> There will be PhD positions available, this year. We are looking for talented students motivated by computational and medicinal chemistry and molecular biology. We will soon have PhD positions in data science and biotechnology Our latest stories: -> Review on structure-function relationship of cation-coupled chloride cotransporters and insights for selective CCC inhibitor design CCCs modulate transport of sodium and/or potassium cations coupled with chloride anions. A growing wealth of evidence has shown their involvement in a great variety of CNS pathologies, which has motivated several drug discovery campaigns targeting CCCs. We link recent cryo-EM data with older biochemical/functional studies on CCCs, we then discuss the impact of this information on the development of selective CCC modulators. Trends Chem. (Link) - On the journal cover! -> Advanced review in DNA and RNA polymerases and the role of computation in their understanding DNA and RNA polymerases are enzymes central to life, whose functions are linked to relevant human diseases, such as cancer and COVID-19, respectively. Pols represent an intense research are in which computation aided explorations have contributed to elucidate experimentally inaccessible atomistic details of Pol function. We examine and discuss advances supported by computational work on the metal aided enzymatic reaction of substrate addition and the conformational rearrangements that accompany this process, along with Pol fidelity and artificial Pol engineering. WIREs Comput Mol Sci. (Link) - On the journal cover! -> Characterization of our novel class of selective NKCC1 inhibitors for the treatment of CNS disorders Intracellular chloride concentration is defective in several neurological disorders. In previous collaborative works we have shown that correction of intracellular chloride concentration through NKCC1 inhibition with our lead compound rescues core Down Syndrome symptoms. In this new collaborative effort we describe in depth the discovery and extensive characterization of our new chemical class of selective NKCC1 inhibitors. Our results further strengthen the potential of our inhibitors for the treatment of brain disorders characterized by defective intracellular chloride concentration. J. Med. Chem. (Link) - On the journal cover! -> Elucidating the functional role of metal ion trafficking in a fundamental metallozyme Recent RNase H1 structures unexpectedly captured multiple metal ions transiently bound near the two metal ion active site. Using state of the art simulation techniques we investigated the functional implications of the exchange of these newly found metal ions at the reaction center. This exciting collaboration lead to the finding that the metal ions' role is crucial for reactant alignment and leaving group departure, also that the solution’s ionic strength tightly regulate the metal ions’ trafficking. ACS Catal. (Link) - On the journal cover! -> Understanding the outer coating monolayer of nanoparticles to increase nanozyme efficiency Gold nanoparticles functionalized with Zn(II) complexes cleave phosphate esthers and nucleic acids, similarly to metallonuclease enzymes. To elucidate the reaction mechanism of these nanocatalysts we have used and integrated approach of microsecond long simulations along with NMR experiments, to investigate the structure and dynamics of the outer coating monolayer of these nanoparticles. This collaborative effort lead to the finding that these nanozyme's mechanism mimics two-metal-ion enzymes for nucleic acid processing. ACS Catal. (Link) - On the journal cover! -> Combining CG MD simulations with ST electron microscopy to uncover how nanoparticles and membranes associate Functionalized metal nanoparticles have shown to be promising candidates as innovative tools in nanomedicine. Although, as with all new technologies, there are many gaps to bridge. In our most recent collaborative effort, we have investigated the association mechanism between nanoparticles and membranes, in order to further optimize this critical interaction. J. Chem. Theory Comput. (Link) - On the journal cover! -> Using a hybrid experimental-computational approach for the study of guanidium-functionalized gold nanoparticles and neutral phospholipid bilayers For the advancement of nanomedical applications, it is necessary to understand and control the interactions between nanoparticles and biological entities. Specifically, nanoparticles that are able to directly target membranes are an important leap forward. Here, we have shown that guanidium-coated gold nanoparticles can bind non-disruptively to neutral liposomes, in contrast to nanoparticles decorated with other positively charged headgroups. Commun. Chem. (Link) -> Reviewing the role of first principles simulations in understanding (bio)catalytic processes Understanding catalysts is fundamental for the design of catalytic systems, enzyme inhibitors or drugs. First principles MD is a powerful technique that combines the description of both nuclear and electronic rearrangements during catalytic reactions. Recently, this tool has only become increasingly attractive due to improvements in accuracy, computing power and algorithmic advances. Chem Catalysis. (Link) -> Nanotron elucidated molecular recognition mechanism In this collaborative effort we showcase our newly developed tool, Nanotron. Nanotron analyses MD simulations of ligand shell-protected nanoparticles and defines their surface morphology and pocket fingerprints of binding cavities in the coating monolayer. Through this tool we have proposed a molecular recognition mechanism between salicylate and host nanoreceptors. J. Phys. Chem. Lett. (Link) -> Dissection of the catalytic mechanism of a relevant metalloprotein Our latest work uses quantum calculations to elucidate HDAC6’s catalytic mechanism. We relied on DFT-based computations to build our understanding. Our findings here could help future studies and drug design efforts for HDAC6’s. ACS Catal. (Link) -> Fundamental principles underlying colloidal stability of metal nanoparticles In our most recent publication, we discuss the dispersivity of nanoparticles at physiological conditions, a critical requirement for the safe implementation of nanoparticles in medical practices. The study combines multiscale simulations and spectroscopy techniques to jointly predict the optimal conditions for nanoparticle stability. Nat. Commun. (Link) -> A novel and selective topoisomerase inhibitor for treating cancer We study the potency and novelty of a new organic scaffold for its selective binding to human topoisomerase II α over β. This inhibitor displays a novel binding mode that enables a new approach for targeting cancerous cells. J. Med. Chem. (Link) -> Discovery of a small molecule drug candidate for selective NKCC1 inhibition in brain disorders Great collaborative effort with top neuroscientist Laura Cancedda on selective inhibitors for NKCC1 trasporter to treat neurodevelopmental disorders - online in Chem (Cell Press) Pushing towards clinical studies - Stay tuned! Chem (Cell Press) (Link) -> Resolving the spatiotemporal location and function of group II introns during splicing. In our most recent work we employ enzymatic assays, X-ray crystallography, and molecular simulations to unravel a proton-triggered conformational rearrangement that takes place between the first and second steps of splicing. Nat. Commun. (Link) -> New compounds to block Topoisomerase II and fight cancer just published in J. Med. Chem. We report on the design, synthesis, dynamic docking, biochemical characterization, and in vivo pharmacokinetics studies of novel topoisomerase II poisons with promising antiproliferative activity to fight cancer. J. Med. Chem. (Link) -> Unraveling the intermittent presence of the third metal ion in the human exonuclease 1. In our most recent publication, by dint of molecular dynamics simulations, we unpuzzle the binding of a third metal ion in the human exo-nuclease 1 in terms of the sidechain flipping of Glu89. J. Am. Chem. Soc. (Link) -> On the computational and experimental efforts for studying lipid plasticity. Our latest account article digs into the importance of molecular dynamics simulations when investigating membrane trafficking and selective hydrolysis of lipids, and the ancillary cooperativity with wet-lab measurements. Acc. Chem. Res. (Link) -> Shedding light on the hydrolysis of nucleic acids In our most recent story, classical and quantum-based molecular simulations are employed to unravel the importance of cation-pi interactions in the hydrolysis of nucleic acids by metal-dependent DNA and RNA nucleases. J. Am. Chem. Soc. (Link) -> Rationalizing the chirality transfer in gold nanoclusters With a combination of NMR techniques and molecular dynamics simulations, this new story sheds light on the chirality transfer of a passivated 38-atom gold nanocluster. Such study addresses the dynamics of the chirality transfer between chiral surfaces and achiral ligands. ACS Nano. (Link) -> Rationally designing gold-supported nanoreceptors Based on molecular dynamics simulations, this article presents the smart design of gold nanoparticles applied to analyte detection. In this study, the functional molecules grafted onto the nanoreceptors are modeled to optimize their affinity. Angewandte Chemie. (Link) -> Towards the smart engineering of functionalized gold nanoparticles A reliable 3D model of functionalized gold nanoparticles is determinant for the knowledge-based design of nanomaterials with novel applications. This article introduces NanoModeler, a webserver for the assembly and parametrization of monolayer-protected gold nanoparticles. J. Chem. Theory Comput. (Link) - On the journal cover! -> Understanding the mechanism of DNA and RNA polymerases Computational approaches, integrated with experimental data, have shed light in recent years on the mechanism of action of DNA and RNA polymerases. This perspective discusses the importance, opportunities and challenges on this growing field. ACS Catal. (Link) -> Unraveling the allosteric communication in Protein Tyrosine Phosphatases This study illustrates the allosteric network and reveals new sites for targeting allosteric inhibitors of Protein Tyrosine Phosphatases (PTPs), explaining the functional influence of a diverse set of disease-associated mutations. Biochemistry, (Link) -> Inhibiting ATP-dependent phosphorylation This study uses a broad set of biophysical analyses to evaluate the use of abietane-type diterpenoids, a biologically active class of phytometabolites with largely nonpolar structures, for the development of pharmaceutically relevant PTP inhibitors. Biochemistry, (Link) -> Metal-ligand interactions in drug design Atomistic understanding of the metal–ligand interactions will help us identify potent metalloenzyme inhibitors and metallodrugs. Our Perspective in Nature Reviews Chemistry, (Link) On the cover of the Journal! Check it out!!! -> Watson&Crick model for DNA: to be or not to be... Our new study on how Polymerases shape the growing DNA has been published in the Journal of the American Chemical Society. A new step forward in understanding how enzymes process DNA and RNA! - (Link) -> Targeting bacterial Topoisomerases ! Our new study, in collaboration with Dr. Miscione at Uni Andes (CO), has been just published as part of the Special Issue "DNA Topoisomerases" in the International Journal of Molecular Sciences - (Link) -> New inhibitors for cancer - targeting topoisomerase II Our new study in collaboration with Dr. C. Sissi at UniPd and Dr. A. Minarini at UniBo has been published in J. Med. Chem. - Link We disclose novel Topoisomerase II poisons with promising antiproliferative activity: -> Two-metal-ion architecture, expanded! Our new study in collaboration with Dr. M. Marcia, at EMBL - Check it out! We report on newly-identified structural elements for DNA and RNA processing in different enzymes. This study has been published on Structure (Cell Press). -> Pocket crosstalk analysis for extended MD trajectories! Check out our newly developed method to analyze long MD trajectories and know about pocket formation, dynamics & allostery! This method is published in ACS Central Science. Link This study will be on the cover of the journal and has been highlighted in First Reactions ACS Central Science, "Toward Understanding “the Ways” of Allosteric Drugs", by R. Amaro 2017 -> Nanoparticles like proteins! Check out our combined computational-experimental work in collaboration with Dr. Mancin and Rastrelli and Univ of Padova, on gold NPs for chemosensing. This study has just been published on Chem (Cell Press) ! - Link It is the Cover Article! -> Fighting melanoma! Check out our new paper on J. Med. Chem. reporting the design and discovery of potent inhibitors of the enzyme Acid Ceramidase - Link -> Opinions&Comments on "dynamic docking" for drug discovery in WIREs Computational Molecular Science, read "Recent advances in dynamic docking for drug discovery" - Link |
