COMPUTATIONAL AND BIOPHYSICAL TOOLS TOWARDS PPIS DRUG DISCOVERY

Maayan Gal and Itai Bloch

Department of Biochemistry, Migal research center, Kiryat Shmona 11016, Israel

Abstract

The biophysical characteristics of protein-protein interactions (PPIs) make the discovery of small molecule inhibitors and their chemical optimization a challenging task. This is mainly due to the complexity involved in characterizing multi-molecular systems and our limited understanding of the physical principles governing PPIs. Even when a preliminary hit, i.e., a molecule that shows weak-medium activity, is found, extensive medicinal chemistry is required in order to optimize the activity of the molecule towards the target system. This last step is time consuming and often done blindly by trial and error. Here we show that the combination of computational tools which are capable of filtering a large library of potential small molecule inhibitors together with biophysical tools is an efficient engine for finding PPI inhibitors and for chemical optimization. In our study we apply this strategy to search and chemically optimize small molecules capable of interfering with two biologically imperative systems. The first system is the interaction of the E3-ligase MDM2 with the transcription factor p53 in order to reactivate the latter tumor suppression activity. The second system is the interaction of the 'program cell death receptor 1' (PD-1) with its ligands PD-L1/2 in order to reactivate T-cells anti-tumor activity by unprecedented small molecule inhibitor. In both of the aforementioned projects we virtually screened a library of 20 million small molecules that were filtered to a final set of virtual hits. Preliminary in vitro hits were then found by screening against the target proteins. Focused and efficient chemical synthesis based on iterative cycles of modelling and biophysical characterization enabled us to rapidly evaluate and elucidate the structural/chemical requirements for the biding and optimize activity. Our improved chemical analogous paves the way for the development of new and novel successful anti-cancer drugs.

Keywords: Drug discovery, Protein interactions, in-silico screening, Biophysics.