Towards Automated Binding Affinity Prediction Using an Iterative Linear Interaction Energy Approach

Binding affinity prediction of potential drugs to target and off-target proteins is an essential asset in drug development. These predictions require the calculation of binding free energies. In such calculations, it is a major challenge to properly account for both the dynamic nature of the protein and the possible variety of ligand-binding orientations, while keeping computational costs tractable. Recently, an iterative Linear Interaction Energy (LIE) approach was introduced, in which results from multiple simulations of a protein-ligand complex are combined into a single binding free energy using a Boltzmann weighting-based scheme. This method was shown to reach experimental accuracy for flexible proteins while retaining the computational efficiency of the general LIE approach. Here, we show that the iterative LIE approach can be used to predict binding affinities in an automated way. A workflow was designed using preselected protein conformations, automated ligand docking and clustering, and a (semi-)automated molecular dynamics simulation setup. We show that using this workflow, binding affinities of aryloxypropanolamines to the malleable Cytochrome P450 2D6 enzyme can be predicted without a priori knowledge of dominant protein-ligand conformations. In addition, we provide an outlook for an approach to assess the quality of the LIE predictions, based on simulation outcomes only.     

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β3‐Adrenoceptor Agonists

Novel compounds were prepared in fair to good yields as human β₃‐adrenoceptor (β₃‐AR) agonists. In particular, aryloxypropanolamines 7 a – d (EC₅₀=0.57–2.1 nM ) and arylethanolamines 12 a , b , e (EC₅₀=6.38–19.4 nM ) were designed to explore the effects of modifications at the right‐hand side of these molecules on their activity as β₃‐AR agonists. Piperidine sulfonamides 15 a – c , e – g (EC₅₀=6.1–36.2 nM ) and piperazine sulfonamide derivatives 20 – 29 (EC₅₀=1.79–49.3 nM ) were examined as compounds bearing a non‐aromatic linker on the right‐ and left‐hand sides of the molecules. Some piperazine sulfonamides were found to be potent and selective β₃‐AR agonists, even if the amine nitrogen atom is tertiary and not secondary, as is the case for all β₃‐AR agonists reported so far. (S)‐3‐{4‐{N‐{4‐{2‐[2‐Hydroxy‐3‐(4‐hydroxyphenoxy)propylamino]ethyl}phenyl}sulfamoyl}phenoxy}propanoic acid ( 7 d ; EC₅₀=0.57 nM ), (R)‐N‐{4‐[2‐(2‐hydroxy‐2‐phenylethylamino)ethyl]phenyl}‐4‐(3‐octylureido)benzenesulfonamide ( 12 e ; EC₅₀=6.38 nM ), (R)‐2‐[1‐(4‐methoxyphenylsulfonyl)piperidin‐4‐ylamino]‐1‐phenylethanol ( 15 f ; EC₅₀=6.1 nM ), and (S)‐4‐{2‐hydroxy‐3‐[4‐(4‐methoxyphenylsulfonyl)piperazin‐1‐yl]propoxy}phenol ( 25 ; EC₅₀=1.79 nM ) were found to be the most potent β₃‐AR agonists of the aryloxypropanolamine, arylethanolamine, piperidine sulfonamide, and piperazine sulfonamide classes, respectively. The two most potent compounds were identified as possible candidates for further development of β₃‐AR agonists useful in the treatment of β₃‐AR‐mediated pathological conditions.