PROTAC-Design-Evaluator (PRODE) -- An Advanced Method for in-silico PROTAC design

Abstract

PROTAC (proteolysis-targeting chimeras) is a rapidly evolving technology to target undruggable targets. The mechanism by which this happens is when a bifunctional molecule binds to a target protein and also brings in proximity an E3 ubiquitin ligase to trigger ubiquitination and degradation of the target protein. Yet in-silico driven approaches to design these hetero-bifunctional molecules that have the desired functional properties to induce proximity between the target protein and E3 ligase remains to be established. In this paper we present a novel in-silico method for PROTAC design and to demonstrate the validity of our approach. We show that for a BRD4-VHL PROTAC ternary complex known in the literature, we are able to reproduce the PROTAC binding mode, the structure of ternary complex formed therein and the free energy ({Delta}G) thermodynamics favoring ternary complexation through theoretical computational methodologies. Further, we demonstrate the use of Thermal Titration Molecule Dynamics (TTMD) to differentiate the stability of PROTAC mediated ternary complexes. We employ the proposed methodology to design a PROTAC for a new system of FGFR1-MDM2 to degrade the FGFR1 (Fibroblast growth factor receptor 1) which is overexpressed in cancer. Our work presented here and named as PROTAC-Designer-Evaluator (PRODE) contributes to the growing literature of in-silico approaches to PROTAC design and evaluation by incorporating the latest in-silico methods and demonstrates advancement over previously published PROTAC in-silico literature.