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 x0104, x0161, x0195, x0305 and 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 studies. 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: A Nitrile group, placed at ortho-position to the sulfonamide moiety of fragment x0161, is able to fit a sub pocket located where water molecule W116 (Structure x0336) is located. This substitution can impact favourably ligand binding both from an enthalpic and entropic contributions (i.e. Biophys J. 2015 Feb 17; 108(4): 928–936). Alternatively the Nitrile group can be replaced by a cyclic N-acyl sulfoximine core. It is able to fit a sub pocket located where W116 (Structure x0336) is located. The carbonyl oxygen at the cyclic N-acyl sulfoximine core is able to interact (H bond) with the Gln192 side chain and Thr190 backbone. This group is located in an overlapping region to the occupied volume by the sulfoxide oxigen of DMS901 (structure x0354). The S-attached methyl group of the chiral core (R enantiomer) is interacting with Pro168, while the S-attached oxygen atom is (favourably) directed towards a more solvent exposed area of the binding pocket. At the para-position (to the S-attached sulfoximine substituent) of the aromatic ring, the binding pocket is more shallow and able to accommodate several different structural motifs. Bulky, sp3 rich motifs should be well tolerated in this region and could enable the ideation of structurally diverse lead molecules with good solubility and PK properties. A set 7 and 8 membered rings structures derived from the Crystallography Open Database (stripped of major substituents) were rigidly docked to assess the potential fit to this accessory binding pocket. This approach was used in order to avoid incurring MM minimization artifacts and to quickly get a flavour of interesting substituents worth exploring. The 1,4-oxazepine derivative is inspired from the Crystallography Open Database (ref. 1100289) after QM optimization. The N-attached methyl group is fitting into the hydrophobic pocket delimited by Met165 and Phe181 side chains. Similarly, a polar lipophilic pocket compatible unit, such as a nitrile (R-CN, where R is an aromatic group) has also been seen to explore such a region (fragment x0305). The methyl group attached to the carbon at the 3 position of the oxazepinone is interacting with the Met165 side chain. The oxygen (position 1 of the oxazepinone) is almost coplanar to the aromatic ring, towards the solvent exposed area of the binding pocket. The carbonyl oxygen is placed in a mild polar binding pocket, interacting with a conserved water molecule (W6). Some of the reported oxazepinones might be challenging to synthesize or introduce unwanted complexity in the designed compound (i.e. 3 chiral centers). Alternatively, a sulfonamide to a non cyclic acyl sulfoximine transformation was applied. 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 carbonyl oxygen of the acyl group is interacting with W39 and the amide NH is hydrogen bonded with Glu166 backbone. Pyridine nitrogen is interacting with water molecules W116. We also suggest synthesizing the R enantiomer. Preliminary docking studies suggest that the protein interaction pattern might be different.
Notes: This proposal includes a novel core proposal. The N-acyl sulfoximine core also enables the possibility to explore the impact of chirality (at the sulfur atom) and of the substitution pattern at the S-linked alkyl substituent. A search to find the best substitution pattern is under investigation using a similar approach inspired from Nature, 2019 Feb; 566(7743): 224–229. N-acyl sulfoximine core FF parameters (i.e. bond distances and angles) have been retrieved from the Crystallography Open Database (ref. 1506487). At the present moment, the submitted compound has overall excellent protein fit and balanced predicted DMPK profile. Molecular dynamics simulations are running in order to determine the most probable tautomeric and rotameric state of HIS41. N-acyl sulfoximine core FF parameters (i.e. bond distances and angles) have been retrieved from the Crystallography Open Database (refs. 2009173, 4020573). CALCULATED PROPERTIES (DataWarrior 4.7.2) of the molecule reported in the PDB model are the following: MW: 332.38 Da; clogP: 0.43; HBA: 5; HBD: 0; TPSA: 84.42 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. All submissions are co-authored with Alberto Cuzzolin and Alessandro Deplano.