Prof. Amnon Albeck

Organic chemistry, Peptides and peptidomimetics, Biochemistry, Enzymology, Enzyme mechanisms, Enzyme inhibition, Proteases, Medicinal chemistry, Computational biochemistry.

Particular research areas (projects):

1. Organic synthesis, peptides and peptidomimetics: amino acid- and peptide bond replacement, N- and C-terminal functional groups.
2. Enzyme catalysis and inhibition mechanisms. The catalytic machinery of proteases, acid-base catalysis, pKa and protonation state of catalytic residues, the mechanism of inhibition by unique inhibitors.
3. Development of inhibitors for enzymes with potential therapeutic applications.
4. Computational biochemistry: enzyme mechanisms, development of computer-assisted drug design  tools and their implication in inhibitor- and drug design.
5. Medicinal chemistry: anti-necrotic compounds, anti-cancer Te compounds, treatment for autism.

Interesting? Want to learn more?

Our research focuses on understand enzyme mechanism and inhibition and to design and develop drugs targeted towards enzymes. The research is interdisciplinary in nature, combining synthetic organic chemistry, biochemistry, enzymology, computational chemistry, and cellular biology.

Enzyme Reaction Mechanisms

Understanding the mode of action of enzymes at the molecular level has important potential applications, as it opens up possibilities to selectively control or modulate such activities. This approach is essential for basic research, as well as for the development of new drugs and other biologically active compounds.

We study proteolytic enzymes, enzymes that hydrolyze (cleave) proteins and peptides which are involved in many biological processes. The research combines experimental research with computational biochemistry. Experiments include biochemical analysis, enzyme kinetics, chemical synthesis, and analytical techniques such as NMR and X-ray crystallography.

How does acid/base catalysis in serine proteases really work?

Computational Methods development

Computational tools are very instrumental in enzyme mechanism studies. One of the most usefull methods is QM/MM, which combines in an itterative process QM calculations on a smal active-site molecular cluster and MM calculations for the rest of the protein and its environment. We developed a new methodology, MD-QM/SCRF(VS), which combines molecular dynamics (MD) simulations with quantum mechanical (QM) calculations of the enzyme. In the QM calculations the enzyme is treated as a two layer system: the inner layer, a large molecular cluster simulating the enzyme active site, is explicitly calculated. The outer layer, the rest of the protein and its environment, is treated as a uniform continuum, a "virtual solvent (VS)", characterized by a dielectric constant which is calibrated by experimental data. This methodology has some advantages over common computational tools. It has been successfully applied for the study of structure, protonation states, pKa values and detailed molecular-level mechanisms of enzyme catalysis and inhibition.  

The QM/SCRF(VS) concept

Drug Design and Delivery

This research involves the design and synthesis of enzyme inhibitors, drug candidates and drug delivery systems, as well as evaluation of their activity at various levels, from in-vitro studies to in-vivo animal model experiments.

One project, in collaboration with Prof. Gary Gellerman from Ariel University, focuses on the development of novel methodologies for the preparation of targeted multi-drug delivery systems, with the aim to recruit anti cancer drugs and drug candidates that failed clinical trials due to their toxicity.

Another project, with Prof. Ilana Nathan from Ben Gurion University and Soroka Medical Center, concentrates on understanding basic biological processes involved in necrotic cell death and on the development of protease inhibitors to treat necrosis. This project has produced very encouraging in-vivo results in three animal model systems.

A decade-long collaboration with Prof. Michael Albeck and Prof. Benjamin Sredni from Bar Ilan University deals with the development of tellurium-based bioactive compounds as potential anti-cancer and anti-viral drugs. Here, too, animal studies demonstrated the therapeutic potential of these compounds.

Other projects in the pharmaceutical field and in an industrial application are underway in our lab.

Representative 3D structure of an enzyme active site (cyan) interacting with its inhibitor (magenta). The structure emerged from computational studies. 

Computer-Assisted Drug Design Tools Development

One central research direction in our lab involves the development of novel computer-assisted drug design (CADD) tools to assist medicinal chemists and the pharmaceutical industry in the design of new bioactive compounds. In a project that may help to overcome the problem of mutational drug resistance, led by Prof. Michael Shokhen in our lab, we develop computational tools for the design of new antibacterial and antiviral drugs based on enzyme inhibitors. Common drug design tools deal with non-covalent inhibitors, which eventually suffer from mutational drug resistance. The emergence of resistant bacterial and viral strains, as well as cancer cells, has become a major problem in modern medicine. The methodology we develop is applicable to transition-state analog enzyme inhibitors. These reversible covalent inhibitors interact directly with the catalytic machinery of the enzyme, which is not subject to mutations. While the common CADD tools are either structure-based or ligand / pharmacophore-based methodologies, our approach can be classified as a mechanism-based drug design tool. Indeed, our previous mechanistic studies on enzyme catalysis and inhibition provided the basis for the development of this novel CADD methodology.

A description of the EMBM methodology for virtual screening and rational design of protease inhibitors. 

Peptidomimetics

Peptide analogs, in which one or more functionalities have been altered, are promising for many applications in drug development, diagnostics, and mechanistic studies. We develop innovative synthetic methods for the preparation of such peptide analogs, applying them for the synthesis of novel enzyme inhibitors.

These inhibitors may serve mechanistic research goals, or may be developed for drug discovery projects. Their functional alterations may include the introduction of reactive functional groups to covalently interact with a target enzyme, conversion of a peptide bond to a metabolically stable isostere, or design of scaffolds that mimic small peptides.

Chemo-enzymatic synthesis of a variety of optically active functionalized building blocks for peptidomimetics (red) from a single optically active precursor (blue), obtained by a stereoselective enzymatic hydrolysis of a prochiral starting material (green). 

Looking to the Future

As a research group that combines both experimental and computational research tools, and that emphasizes both basic-mechanistic and applied research, we are committed to the improvement and further development of our drug design computational methodologies and their application in practical drug development projects. Ongoing projects as well as future projects are expected to yield biochemical information and bioactive compounds that together will provide the grounds for the development of new drugs.