Analisi dello spazio conformazionale di PROTAC1 in solvente esplicito per mezzo di modelli di Markov ​

PROTAC1 (PR1) is a Proteolysis targeting chimera (PROTAC), a heterobifunctional molecule capable of inducing intracellular degradation of a target protein. Although PR1 lies in a chemical space that is far from ideal for drug-like properties, it is orally bioavailable. Membrane permeability is strongly influenced by its conformational behavior, which includes the ability to adapt to both the polar aqueous environment outside the cell membrane and the non-polar environment within cell membranes. In this study, we attempted to rationalize the conformational behavior of PR1 mainly in chloroform, mimicking the interior of the cell membrane, but also in water to gain a better understanding of the pharmacokinetic properties of this molecule. From 10 μs simulations in explicit solvent, Markov state models (MSM) were constructed to characterize the metastable states. To our knowledge, this is the first attempt to employ markov state modeling to a non-peptidic organic molecule and in the context of drug discovery of large compounds it may provide a powerful tool regarding the problem of determining relevant conformations. ​