PDB MODELS: Representative molecule bound to the predicted target protein structure is provided. The transformative structural leap from the available fragments is substantial. The representative reported molecule has a tanimito (our own implementation) color/shape overlap > 0.7 with fragments x0161, x0195, x0305, x0946 with a Tanimoto fingerprint (Morgan) overlap < 0.4 with all available fragments. DESIGN RATIONALE: Core modifications are inspired from a crystallographic fragments structure review and driven by contact and conformational analysis. Initial guess of the ligand binding conformation into the protein binding pocket obtained using AutoDock Vina. Structure was then refined running a MM energy minimization (Amber 99 FF), tethering (using harmonic restraints) binding pockets and ligand heavy atoms. The output is thoroughly validated using knowledge based methods (i.e. small and bio-molecules crystal structure information). J. Chem. Inf. Model., 2008, 48 (1), pp 1–24 and the Crystallography Open Database, J. Appl. Cryst. 42, 726-729. BRIEF DESCRIPTION: Fluorination (at the 3 position of the tetrahydroquinoline core) to increase ligand volume occupancy with no disruption of the water network surrounding the binding pocket (MD simulation analysis). Methylation at the 4 position of the tetrahydroquinoline core. The methyl group will adopt an equatorial preferred orientation (i.e. Crystallography Open Database ref. 2213899) impacting favourably ligand binding both from an enthalpic and entropic contributions (i.e. Biophys J. 2015 Feb 17; 108(4): 928–936). Similarly, a polar lipophilic pocket compatible unit, such as a nitrile (R-CN, where R is an aromatic group) has also been seen to occupy that subpocket (fragment x0305). No step-change in activities between the two enantiomers has been predicted. A single methyl group substituent will tend to adopt an axial preferred orientation. Gem-dimethyl group at the 4 position of the tetrahydroquinoline core is tolerated. Fluorination at the 5 position is placed in a mildly polar region of the binding pocket (small but significant enthalpic contribution). The alkyl portion of the tetrahydropyranyl moiety (position 1 of the tetrahydroquinoline) is able to interact with the Met49 side chain (hydrophobic interaction) while exposing the polar cyclic ether moiety towards the solvent exposed region. In particular the tetrahydropyran oxygen is interacting with the Ser46 side chain (favorable polar interaction). Such an interaction is quite solvent exposed therefore providing a negligible impact (enthalpic contribution) to the ligand binding energy. The tetrahydropyran oxygen is located in an overlapping region to the carbonyl oxygen of the N-acyl piperazine moiety (structure ref. x0354). In order to reduce a potential CYP induction liability a sulfonamide to the sulfoximine transformation was applied (Org. Chem. Front., 2019,6, 1319-1324). The S-attached methyl group of the chiral group (S enantiomer) is interacting with Pro168, while the S-attached oxygen atom is directed towards a more solvent exposed area. The sulfoximine NH is interacting with the Glu166 backbone (Hydrogen bond) and thus having a similar protein-ligand interaction pattern of the parent fragment. Pyridine nitrogen can interact with water molecule W116.
NOTES: The tetrahydropyranyl moiety can undergo N-dealkylation and aliphatic hydroxylation of carbon alpha to secondary or tertiary alkyl-N. Alternative substituents to the tetrahydropyranyl moiety and of the sulfonamide group (7 position of the tetrahydroquinoline core) are under evaluation at the moment using a similar approach inspired from Nature, 2019 Feb; 566(7743): 224–229. Sulfoximine FF parameters (i.e. bond distances and angles) have been retrieved from the Crystallography Open Database (ref. 1506487, 2009173, 4020573) and then refined using a QM approach. In the context of drug design, the conformation a small molecule adopts when bound to a protein target is of fundamental importance. The proposed modifications were designed in order to allow the molecules to adopt the desired shape with little or no energetic penalty upon binding. Within this set of molecules, some derivatives might be more challenging to synthesize than others (i.e. pyridine derivatives). CALCULATED PROPERTIES (DataWarrior 4.7.2) of the molecule reported in the PDB model are the following: MW: 345.41 Da; clogP: 1.87; HBA: 4; HBD: 1; TPSA: 75 Angstroms squared; No mutagenic, tumorigenic or irritant flags detected. A detailed overview of the molecular properties of all the submitted molecules will be reported in the forum, at a later stage. PREDICTED AFFINITY CLASS: Promising high nanomolar binder. A detailed overview of the developed ML model will be reported in the discussion forum.