Submission Details

Design Rationale:

CHEMICAL PROFILE Molecules designed by Benjamin P. Brown Graduate student in the laboratory of Jens Meiler, Ph.D. Email: benjamin.p.brown@vanderbilt.edu Notes on the chemical profile: Design protocol: Fragments co-crystalized with COVID-19 main protease (released by the Diamond Xchem group) served as starting scaffolds for combinatorial chemistry with an in-development Meiler Lab algorithm called BCL::LinkFragments. After filtering ~800,000 fragment combinations for physchem properties, geometry (i.e. pocket complementarity), and predicted activity, we performed focused library design (BCL::FocusedLibraryDesign) on a subset of the best new molecules. The variation of this algorithm utilized for this study incorporated a conventional supervised feed-forward deep neural network (DNN) as a pose-dependent protein-ligand interface scorer. Fragments were perturbed in a Monte Carlo - Metropolis fashion using alchemical transformations, and refined at each step to minimize clashes, optimize pose orientation, and filter out unstable/non-drug-like modifications. Molecules are optimized for clash resolution and interaction score. The best molecules undergo a final short run of BCL::FocusedLibraryDesign, and minor manual modifications are selectively made to intentionally increase probing of the structure-activity relationship (SAR). Finally, compounds are re-docked with RosettaLigand. The top-scoring complex is taken to be the final pose. Note that in multiple instances there is more than 1 well-populated binding pose. Here, we simply took the best scoring pose. Also note that the pose optimizing the RosettaLigand score is not the same pose that optimizes the DNN score. Nomenclature: XLogP, XLogS, and XdG_Hyd are LogP, LogS, and dg_hydration (kcal/mol) predictions made using a multi-tasking deep neural network trained in the BCL. LipinksiDruglike returns 1 if there are less than 2 Lipinksi violations. RS_Score_Raw and RSCONVOL_Score_Raw are two novel (in preparation) scoring functions developed in the BCL that use a DNN to prediction the binding affinity of small molecules to receptors (in units of -log(Kd)) using either pose-dependent or pose-dependent+pose-independent protein-ligand hybrid descriptors. RS_AD and RSCONVOL_AD are applicability domain (AD) metrics of the DNN scores; values less_equal 0.90 are generally considered good and mean we trust the corresponding activity prediction reasonably well. RosettaLigandInterfaceScore is the interface_delta_X (protein-ligand interaction score) from Rosetta v3.11 of the best pose in Talaris2014 Rosetta energy units (REU). MoleculeComplexity is a metric by Ertl. et al., 2009, Journal of Cheminformatics, and generally less than 2.5 indicates the molecule is reasonably synthesizable.

Other Notes:

My favorite molecule from this cluster is n1cc([nH]c1)c1cc(Oc2c3[nH]cc(CCC)c3cc(c2)F)ncc1 It has the best scores, the best score vs. rmsd plot during the redocking, and it has a nice 3 ring structure with good predicted physchem properties. Score vs rmsd plots and docking models available upon request. Below are the specs for each molecule in the order in which they were uploaded. Please contact with questions. Activity Predictions RosettaLigandInterfaceScore: -12.08 (REU) RS_Score_Raw: 6.76163 (applicability domain score: 0.261149) RSCONVOL_Score_Raw: 7.55545 (applicability domain score: 0.991973) Property Predictions XLogP: 2.92427 XLogS: -6.07145 XdG_Hyd: -7.45068 MoleculeComplexity: 1.1981 Additional Properties Weight: 369.24 Number of rotatable bonds: 4 TPSA: 47.14 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -12.517 (REU) RS_Score_Raw: 6.25753 (applicability domain score: 0.253287) RSCONVOL_Score_Raw: 7.32292 (applicability domain score: 0.991083) Property Predictions XLogP: 2.44264 XLogS: -5.5844 XdG_Hyd: -7.01877 MoleculeComplexity: 1.17459 Additional Properties Weight: 320.34 Number of rotatable bonds: 4 TPSA: 37.91 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 3 Activity Predictions RosettaLigandInterfaceScore: -12.14 (REU) RS_Score_Raw: 5.8494 (applicability domain score: 0.23836) RSCONVOL_Score_Raw: 7.37364 (applicability domain score: 0.991409) Property Predictions XLogP: 2.60121 XLogS: -6.06125 XdG_Hyd: -7.76002 MoleculeComplexity: 1.17459 Additional Properties Weight: 336.79 Number of rotatable bonds: 4 TPSA: 37.91 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 3 Activity Predictions RosettaLigandInterfaceScore: -12.577 (REU) RS_Score_Raw: 6.3585 (applicability domain score: 0.274693) RSCONVOL_Score_Raw: 7.22882 (applicability domain score: 0.988912) Property Predictions XLogP: 2.70259 XLogS: -5.87205 XdG_Hyd: -7.98315 MoleculeComplexity: 1.17459 Additional Properties Weight: 318.8 Number of rotatable bonds: 4 TPSA: 37.91 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 3 Activity Predictions RosettaLigandInterfaceScore: -11.923 (REU) RS_Score_Raw: 6.75271 (applicability domain score: 0.334768) RSCONVOL_Score_Raw: 7.86814 (applicability domain score: 0.990137) Property Predictions XLogP: 2.93912 XLogS: -6.48271 XdG_Hyd: -9.37125 MoleculeComplexity: 1.34182 Additional Properties Weight: 384.87 Number of rotatable bonds: 6 TPSA: 66.59 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 5 Activity Predictions RosettaLigandInterfaceScore: -14.685 (REU) RS_Score_Raw: 6.49276 (applicability domain score: 0.314137) RSCONVOL_Score_Raw: 8.02826 (applicability domain score: 0.990116) Property Predictions XLogP: 2.49958 XLogS: -6.094 XdG_Hyd: -10.1356 MoleculeComplexity: 1.34182 Additional Properties Weight: 384.87 Number of rotatable bonds: 6 TPSA: 66.59 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 5 Activity Predictions RosettaLigandInterfaceScore: -16.807 (REU) RS_Score_Raw: 5.92524 (applicability domain score: 0.510346) RSCONVOL_Score_Raw: 7.64549 (applicability domain score: 0.989398) Property Predictions XLogP: 2.24109 XLogS: -5.1411 XdG_Hyd: -10.1389 MoleculeComplexity: 1.26941 Additional Properties Weight: 336.4 Number of rotatable bonds: 5 TPSA: 66.59 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 5 Activity Predictions RosettaLigandInterfaceScore: -15.13 (REU) RS_Score_Raw: 5.73459 (applicability domain score: 0.162697) RSCONVOL_Score_Raw: 7.50566 (applicability domain score: 0.990456) Property Predictions XLogP: 2.72652 XLogS: -5.57505 XdG_Hyd: -9.15365 MoleculeComplexity: 1.26941 Additional Properties Weight: 336.4 Number of rotatable bonds: 5 TPSA: 66.59 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 5 Activity Predictions RosettaLigandInterfaceScore: -17.03 (REU) RS_Score_Raw: 6.1949 (applicability domain score: 0.363197) RSCONVOL_Score_Raw: 8.08725 (applicability domain score: 0.990248) Property Predictions XLogP: 2.7666 XLogS: -6.32435 XdG_Hyd: -9.9366 MoleculeComplexity: 1.26941 Additional Properties Weight: 370.84 Number of rotatable bonds: 5 TPSA: 66.59 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 5 Activity Predictions RosettaLigandInterfaceScore: -19.111 (REU) RS_Score_Raw: 6.41268 (applicability domain score: 0.297015) RSCONVOL_Score_Raw: 7.7947 (applicability domain score: 0.98975) Property Predictions XLogP: 2.6132 XLogS: -5.65798 XdG_Hyd: -9.64646 MoleculeComplexity: 1.26941 Additional Properties Weight: 336.4 Number of rotatable bonds: 5 TPSA: 66.59 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 5 Activity Predictions RosettaLigandInterfaceScore: -17.358 (REU) RS_Score_Raw: 6.10013 (applicability domain score: 0.272767) RSCONVOL_Score_Raw: 7.78822 (applicability domain score: 0.991126) Property Predictions XLogP: 2.45304 XLogS: -5.3031 XdG_Hyd: -9.57975 MoleculeComplexity: 1.1981 Additional Properties Weight: 322.37 Number of rotatable bonds: 4 TPSA: 66.59 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 5 Activity Predictions RosettaLigandInterfaceScore: -13.107 (REU) RS_Score_Raw: 5.852 (applicability domain score: 0.219974) RSCONVOL_Score_Raw: 7.31848 (applicability domain score: 0.987229) Property Predictions XLogP: 2.39837 XLogS: -5.76742 XdG_Hyd: -9.03968 MoleculeComplexity: 1.08192 Additional Properties Weight: 384.65 Number of rotatable bonds: 3 TPSA: 49.94 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -13.513 (REU) RS_Score_Raw: 6.08363 (applicability domain score: 0.130782) RSCONVOL_Score_Raw: 7.44008 (applicability domain score: 0.990077) Property Predictions XLogP: 2.51603 XLogS: -6.15412 XdG_Hyd: -9.10541 MoleculeComplexity: 1.15121 Additional Properties Weight: 398.68 Number of rotatable bonds: 4 TPSA: 49.94 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -12.825 (REU) RS_Score_Raw: 5.3997 (applicability domain score: 0.109614) RSCONVOL_Score_Raw: 6.25542 (applicability domain score: 0.990913) Property Predictions XLogP: 1.61069 XLogS: -4.90338 XdG_Hyd: -9.85901 MoleculeComplexity: 1.24552 Additional Properties Weight: 348.44 Number of rotatable bonds: 4 TPSA: 109.25 Number of hydrogen bond donors: 3 Number of hydrogen bond acceptors: 6 Activity Predictions RosettaLigandInterfaceScore: -13.078 (REU) RS_Score_Raw: 5.35897 (applicability domain score: 0.100965) RSCONVOL_Score_Raw: 6.61785 (applicability domain score: 0.992248) Property Predictions XLogP: 1.41888 XLogS: -4.8388 XdG_Hyd: -9.1217 MoleculeComplexity: 1.22174 Additional Properties Weight: 349.42 Number of rotatable bonds: 4 TPSA: 106.45 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 6 Activity Predictions RosettaLigandInterfaceScore: -13.485 (REU) RS_Score_Raw: 6.51648 (applicability domain score: 0.16093) RSCONVOL_Score_Raw: 6.51444 (applicability domain score: 0.99109) Property Predictions XLogP: 1.50913 XLogS: -5.12318 XdG_Hyd: -8.84141 MoleculeComplexity: 1.29343 Additional Properties Weight: 363.45 Number of rotatable bonds: 5 TPSA: 106.45 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 6 Activity Predictions RosettaLigandInterfaceScore: -17.74 (REU) RS_Score_Raw: 6.08218 (applicability domain score: 0.340075) RSCONVOL_Score_Raw: 7.96749 (applicability domain score: 0.991396) Property Predictions XLogP: 2.76833 XLogS: -5.49181 XdG_Hyd: -8.66977 MoleculeComplexity: 1.1981 Additional Properties Weight: 340.36 Number of rotatable bonds: 4 TPSA: 66.59 Number of hydrogen bond donors: 2 Number of hydrogen bond acceptors: 5 Activity Predictions RosettaLigandInterfaceScore: -13.288 (REU) RS_Score_Raw: 5.84308 (applicability domain score: 0.174595) RSCONVOL_Score_Raw: 7.21756 (applicability domain score: 0.985055) Property Predictions XLogP: 2.86578 XLogS: -5.00938 XdG_Hyd: -6.38635 MoleculeComplexity: 1.10487 Additional Properties Weight: 288.32 Number of rotatable bonds: 3 TPSA: 37.91 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 3 Activity Predictions RosettaLigandInterfaceScore: -8.697 (REU) RS_Score_Raw: 5.05539 (applicability domain score: 0.733867) RSCONVOL_Score_Raw: 7.6994 (applicability domain score: 0.981906) Property Predictions XLogP: 2.26366 XLogS: -5.21956 XdG_Hyd: -7.78797 MoleculeComplexity: 1.03647 Additional Properties Weight: 310.27 Number of rotatable bonds: 3 TPSA: 37.91 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 3 Activity Predictions RosettaLigandInterfaceScore: -11.74 (REU) RS_Score_Raw: 6.47577 (applicability domain score: 0.274515) RSCONVOL_Score_Raw: 7.93543 (applicability domain score: 0.989631) Property Predictions XLogP: 1.55144 XLogS: -4.08766 XdG_Hyd: -9.6183 MoleculeComplexity: 1.31757 Additional Properties Weight: 337.86 Number of rotatable bonds: 3 TPSA: 39.34 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -14.201 (REU) RS_Score_Raw: 7.58636 (applicability domain score: 0.238775) RSCONVOL_Score_Raw: 7.72868 (applicability domain score: 0.987181) Property Predictions XLogP: 1.25889 XLogS: -3.41582 XdG_Hyd: -9.99014 MoleculeComplexity: 1.31757 Additional Properties Weight: 303.42 Number of rotatable bonds: 3 TPSA: 39.34 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -14.456 (REU) RS_Score_Raw: 6.83542 (applicability domain score: 0.37257) RSCONVOL_Score_Raw: 7.47309 (applicability domain score: 0.989646) Property Predictions XLogP: 1.40228 XLogS: -3.69536 XdG_Hyd: -9.45696 MoleculeComplexity: 1.39067 Additional Properties Weight: 317.45 Number of rotatable bonds: 4 TPSA: 39.34 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -12.006 (REU) RS_Score_Raw: 7.29346 (applicability domain score: 0.345143) RSCONVOL_Score_Raw: 7.64988 (applicability domain score: 0.990919) Property Predictions XLogP: 1.68045 XLogS: -4.27702 XdG_Hyd: -9.29117 MoleculeComplexity: 1.39067 Additional Properties Weight: 351.89 Number of rotatable bonds: 4 TPSA: 39.34 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -8.914 (REU) RS_Score_Raw: 6.3291 (applicability domain score: 0.492092) RSCONVOL_Score_Raw: 7.84082 (applicability domain score: 0.987767) Property Predictions XLogP: 1.37568 XLogS: -3.93802 XdG_Hyd: -9.63418 MoleculeComplexity: 1.24552 Additional Properties Weight: 343.36 Number of rotatable bonds: 3 TPSA: 39.34 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -14.025 (REU) RS_Score_Raw: 7.13129 (applicability domain score: 0.149664) RSCONVOL_Score_Raw: 7.68397 (applicability domain score: 0.980278) Property Predictions XLogP: 1.95163 XLogS: -4.01976 XdG_Hyd: -8.72104 MoleculeComplexity: 1.29343 Additional Properties Weight: 304.4 Number of rotatable bonds: 3 TPSA: 45.33 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -11.927 (REU) RS_Score_Raw: 7.0492 (applicability domain score: 0.36822) RSCONVOL_Score_Raw: 8.2017 (applicability domain score: 0.982755) Property Predictions XLogP: 2.27683 XLogS: -4.68786 XdG_Hyd: -8.7055 MoleculeComplexity: 1.29343 Additional Properties Weight: 338.84 Number of rotatable bonds: 3 TPSA: 45.33 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -15.102 (REU) RS_Score_Raw: 7.36092 (applicability domain score: 0.303499) RSCONVOL_Score_Raw: 7.56207 (applicability domain score: 0.983709) Property Predictions XLogP: 2.14681 XLogS: -4.33894 XdG_Hyd: -8.52068 MoleculeComplexity: 1.36619 Additional Properties Weight: 318.43 Number of rotatable bonds: 4 TPSA: 45.33 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -15.187 (REU) RS_Score_Raw: 7.89402 (applicability domain score: 0.262201) RSCONVOL_Score_Raw: 7.94783 (applicability domain score: 0.986366) Property Predictions XLogP: 2.09589 XLogS: -4.86162 XdG_Hyd: -7.79618 MoleculeComplexity: 1.36619 Additional Properties Weight: 352.87 Number of rotatable bonds: 4 TPSA: 45.33 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4 Activity Predictions RosettaLigandInterfaceScore: -13.265 (REU) RS_Score_Raw: 7.82219 (applicability domain score: 0.429373) RSCONVOL_Score_Raw: 8.31348 (applicability domain score: 0.988895) Property Predictions XLogP: 2.29066 XLogS: -5.5257 XdG_Hyd: -7.81457 MoleculeComplexity: 1.36619 Additional Properties Weight: 387.31 Number of rotatable bonds: 4 TPSA: 45.33 Number of hydrogen bond donors: 1 Number of hydrogen bond acceptors: 4

Inspired By:

AAR-POS-d2a4d1df-2

AAR-POS-d2a4d1df-18

MAK-UNK-6435e6c2-8

AAR-POS-d2a4d1df-15