Searching for allosteric sites of the protein kinase family and design of potential drugs

Prof. Jaime Rubio-Martinez
Jaime.rubio@ub.edu
http://www.ub.edu/cadrugdesign/index.html

Details

In recent years, one of the most important target family that have attracted attention for the pharmaceutical industry is the protein kinases family. In 2002 Manning et al. published a study in which they identified 518 genes corresponding to protein kinases in the human genome, which constitutes about 2% of the total genome [1]. Since then, its relevant role has been established in numerous diseases, including cancer [2]. However, kinases present a high degree of conservation of their global three-dimensional structure and have an important lack of structural diversity in the active site, making the design of selective therapeutic inhibitors a very difficult task. For these reasons there is an increasing interest in the design of new compounds with allosteric action mechanism. However, deciphering allosteric or cryptic binding sites has been proves as a difficult job. In the present project we will address this problem using different methodologies recently developed in our research group.

Therefore, Molecular Dynamics (MD) simulations in conjunction with a cosolvent approach and the ‘fragment dissolved Molecular Dynamics’ (fdMD), a method based on multiple solvated molecules around the target protein, will be used to determine possible allosteric binding sites for several members of the protein kinases family and other protein families to design novel drugs that overcome resistance of current treatments. Furthermore, an Artificial Intelligence (AI) approach will be applied for the identification of potential new drugs using the generated data.

• [1] Manning, G., et al., The protein kinase complement of the human genome. Science. (2002).
• [2] Fleuren, EDG., Zhang, L., Wu, J., Roger J. Daly, RJ. The kinome ‘at large’ in cáncer. Nature Reviews Cancer. (2016)

Job position description

The Modelling of Biological Systems and Drug Design research group associated to the Materials Science and Physical Chemistry department at the University of Barcelona (UB) and to the Institute of Theoretical and Computational Chemistry (IQTCUB) (http://www.ub.edu/cadrugdesign/index.html) was created in 2002. The group has extensive experience in the field of Computational Chemistry and Molecular Modelling and in the use of structure-based drug design methodology for the design of new compounds with possible pharmacological activity. The main goal of the group is the design, using molecular modeling techniques, of compounds with pharmacological activity. Taking advantage of our previous experience we are also working in the development of new computational tools to make easier the drug design process and to increase its effectivity. Furthermore, we promote interdisciplinary research by means of collaborations with experimental groups that are basically working in protein targets related to the cancer disease. Because of this cooperation, we found promising compounds for many targets that show µMolar activity in in vitro assays and we are currently synthesizing new compounds to increase its biological activity.

The group is seeking a PhD student with a degree in Chemistry, Physics or Biochemistry and with a Master related to the use of computational methods in Molecular Modeling. We are interested in bringing people with different motivations to exploiting various cutting-edge Drug Design technologies for the design and development of new compounds targeting allosteric sites of protein kinase family. The PhD student will perform a temporary stay in the evotec company (www.evotec.com ).

Summary of conditions

The project proposal is included in the DOCTORAL INPhINIT FELLOWSHIPS PROGRAMME – INCOMING FRAME, more information at: https://obrasociallacaixa.org/en/investigacion-y-becas/becas-de-la-caixa/doctorado-inphinit/incoming

Contract Length: 3 years

Estimated Incorporation date: From July to September 2020