1. Metalloenzyme inhibitors against cancer
Approximately one third of the known enzymes contain a metal ion in its structures, which may act as a catalytic cofactor or as structural stabilizer. These are called “metalloenzymes”. Two families of metalloenzymes, the matrix metalloproteinases (MMPs) and carbonic anhydrases (CAs), are involved in tumor development and progression peocesses, and therefore they are targets of research.
Our aim is to reduce, selectively, the activity of these enzymes and thus stop tumor progression. For that, we try to develop specific inhibitors of these metalloenzymes. The use of computational tools to predict the properties and interaction of new molecules with the enzymes (molecular modeling) is fundamental for the design of new potential drugs against cancer. These new compounds are then synthesized in our lab, and tested towards the biological targets by our collaborators.
We expect to develop low molecular-weight compounds (so-called “small molecules”), presenting high inhibitory activity (IC50 values in nano- or subnanomolar range) towards the MMPs and/or CAs related with cancer.
Achieving our goals in this project, we hope to contribute for the development of a new generation of drugs more directed to the causes of the pathology, and thus avoid some of the side effects observed in the current chemotherapy treatments.
Entities involved: CQE-IST; Faculty of Pharmacy of the University of Pisa (Italy).
2. New drugs against Alzheimer's disease
Alzheimer’s disease (AD) is a multifactorial mental dysfunction. It is the most common cause of dementia among elderly people, and the fourth cause of death in the western countries. In spite of the hundredth anniversary since it was first discovered and described, and all the efforts of medicinal chemists to find and efficient therapy to fight AD, to date only palliative drugs are in clinical use to treat the symptoms.
According to a new emerging ideology in this field, the simultaneous targeting of the several biological factors contributing to the pathology may be the best strategy, rather than the “one molecule, one target” paradigm. This project is based on this assumption, and we try to develop multi-functional compounds targeting several biological molecules. Such are the acetylcholinesterase (AChE), β-secretase (BACE1) and γ-secretase. Making use of molecular modeling tools, we design and prepare inhibitors able to efficiently and simultaneously block the activity of these enzymes in the brain, and thus stop, and, eventually, invert the symptoms of AD.
Achieving our goals in this project, we hope to develop a new generation of multi-target disease-modifying agents, able to simultaneously block several molecular events involved in the pathogenesis of AD. Doing so, these compounds are expected to be more efficient in treating this disease.
With this project we hope to contribute for the development of a future therapy able to stabilize and definitive cure of this devastating disease, which, directly or indirectly, may affect all of us.
Entities involved: CQE-IST; Faculty of Pharmacy of the University of Bologna (Italy); Faculty of Sciences of the University of Lisbon (Portugal)