Submission Details

Design Rationale:

################### # CHEMICAL PROFILE # Cluster 1 # # 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 to the PDB by von Grelft group) served as starting # scaffolds for redesign with an in-development Meiler Lab algorithm called BCL::FocusedLibraryDesign. 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. The best optimizations by QSAR/QSPR analysis # are recombined with BCL::LinkFragments, an in-development combinatorial chemistry algorithm. Again, 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. # # 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:

Computed activities / properties in the order according to upload: :Activity Predictions -RosettaLigandInterfaceScore: -16.152 (REU) -RS_Score_Raw: 6.48735 (applicability domain score: 0.89146) -RSCONVOL_Score_Raw: 7.39091 (applicability domain score: 0.981741) - -Property Predictions -XLogP: 2.07121 -XLogS: -4.82529 -XdG_Hyd: -11.6934 -MoleculeComplexity: 0.987633 - -Additional Properties: -Weight: 379.48 -Number of rotatable bonds: 8 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: - :Activity Predictions -RosettaLigandInterfaceScore: -15.286 (REU) -RS_Score_Raw: 6.54986 (applicability domain score: 0.787665) -RSCONVOL_Score_Raw: 7.525 (applicability domain score: 0.982565) - -Property Predictions -XLogP: 2.15485 -XLogS: -5.04635 -XdG_Hyd: -11.1899 -MoleculeComplexity: 0.987633 - -Additional Properties -Weight: 397.47 -Number of rotatable bonds: 8 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -16.543 (REU) -RS_Score_Raw: 6.60143 (applicability domain score: 0.778084) -RSCONVOL_Score_Raw: 7.62543 (applicability domain score: 0.982361) - -Property Predictions -XLogP: 2.2056 -XLogS: -5.45095 -XdG_Hyd: -11.4353 -MoleculeComplexity: 0.987633 - -Additional Properties -Weight: 413.92 -Number of rotatable bonds: 8 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -13.34 (REU) -RS_Score_Raw: 7.00759 (applicability domain score: 0.597647) -RSCONVOL_Score_Raw: 6.64639 (applicability domain score: 0.986738) - -Property Predictions -XLogP: 1.75697 -XLogS: -4.35601 -XdG_Hyd: -11.4335 -MoleculeComplexity: 0.962834 - -Additional Properties -Weight: 376.45 -Number of rotatable bonds: 8 -TPSA: 83.12 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -13.647 (REU) -RS_Score_Raw: 6.93176 (applicability domain score: 0.798516) -RSCONVOL_Score_Raw: 7.64258 (applicability domain score: 0.985643) - -Property Predictions -XLogP: 2.10727 -XLogS: -5.2988 -XdG_Hyd: -11.0631 -MoleculeComplexity: 0.987633 - -Additional Properties -Weight: 415.46 -Number of rotatable bonds: 8 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -13.937 (REU) -RS_Score_Raw: 7.28463 (applicability domain score: 0.900659) -RSCONVOL_Score_Raw: 7.7896 (applicability domain score: 0.984814) - -Property Predictions -XLogP: 2.23515 -XLogS: -5.66891 -XdG_Hyd: -11.4186 -MoleculeComplexity: 0.987633 - -Additional Properties -Weight: 431.91 -Number of rotatable bonds: 8 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -15.954 (REU) -RS_Score_Raw: 6.93725 (applicability domain score: 0.514942) -RSCONVOL_Score_Raw: 7.25256 (applicability domain score: 0.984816) - -Property Predictions -XLogP: 2.14437 -XLogS: -5.33535 -XdG_Hyd: -11.5828 -MoleculeComplexity: 1.06264 - -Additional Properties -Weight: 411.5 -Number of rotatable bonds: 8 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -18.98 (REU) -RS_Score_Raw: 7.01249 (applicability domain score: 0.770426) -RSCONVOL_Score_Raw: 7.15604 (applicability domain score: 0.987427) - -Property Predictions -XLogP: 2.21693 -XLogS: -5.56776 -XdG_Hyd: -11.5255 -MoleculeComplexity: 1.13852 - -Additional Properties -Weight: 425.53 -Number of rotatable bonds: 9 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -19.471 (REU) -RS_Score_Raw: 6.56658 (applicability domain score: 0.876018) -RSCONVOL_Score_Raw: 7.07678 (applicability domain score: 0.986725) - -Property Predictions -XLogP: 2.15953 -XLogS: -5.29409 -XdG_Hyd: -11.4419 -MoleculeComplexity: 1.13852 - -Additional Properties -Weight: 407.54 -Number of rotatable bonds: 9 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -14.941 (REU) -RS_Score_Raw: 5.88243 (applicability domain score: 0.780581) -RSCONVOL_Score_Raw: 6.34642 (applicability domain score: 0.986829) - -Property Predictions -XLogP: 1.73388 -XLogS: -4.34594 -XdG_Hyd: -12.0463 -MoleculeComplexity: 1.03754 - -Additional Properties -Weight: 372.49 -Number of rotatable bonds: 8 -TPSA: 83.12 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -16.531 (REU) -RS_Score_Raw: 6.62222 (applicability domain score: 0.585752) -RSCONVOL_Score_Raw: 7.47713 (applicability domain score: 0.983996) - -Property Predictions -XLogP: 2.50793 -XLogS: -5.32525 -XdG_Hyd: -10.7334 -MoleculeComplexity: 0.987633 - -Additional Properties -Weight: 421.92 -Number of rotatable bonds: 9 -TPSA: 99.93 -Number of hydrogen bond donors: 2 -Number of hydrogen bond acceptors: 7 - :Activity Predictions -RosettaLigandInterfaceScore: -16.618 (REU) -RS_Score_Raw: 6.80076 (applicability domain score: 0.892186) -RSCONVOL_Score_Raw: 6.39721 (applicability domain score: 0.98919) - -Property Predictions -XLogP: 1.83485 -XLogS: -4.5458 -XdG_Hyd: -11.1643 -MoleculeComplexity: 1.11313 - -Additional Properties -Weight: 386.52 -Number of rotatable bonds: 9 -TPSA: 83.12 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -16.239 (REU) -RS_Score_Raw: 6.26202 (applicability domain score: 0.62743) -RSCONVOL_Score_Raw: 7.46305 (applicability domain score: 0.985467) - -Property Predictions -XLogP: 2.1817 -XLogS: -5.28931 -XdG_Hyd: -11.9387 -MoleculeComplexity: 1.01254 - -Additional Properties -Weight: 420.94 -Number of rotatable bonds: 9 -TPSA: 102.73 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 7 - :Activity Predictions -RosettaLigandInterfaceScore: -14.67 (REU) -RS_Score_Raw: 6.17854 (applicability domain score: 0.704534) -RSCONVOL_Score_Raw: 7.45185 (applicability domain score: 0.981197) - -Property Predictions -XLogP: 2.67388 -XLogS: -5.49351 -XdG_Hyd: -9.88161 -MoleculeComplexity: 0.962834 - -Additional Properties -Weight: 414.9 -Number of rotatable bonds: 8 -TPSA: 76.14 -Number of hydrogen bond donors: 2 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -14.144 (REU) -RS_Score_Raw: 6.42592 (applicability domain score: 0.756836) -RSCONVOL_Score_Raw: 7.45845 (applicability domain score: 0.983359) - -Property Predictions -XLogP: 2.20671 -XLogS: -5.44193 -XdG_Hyd: -11.4221 -MoleculeComplexity: 0.987633 - -Additional Properties -Weight: 413.92 -Number of rotatable bonds: 8 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -12.367 (REU) -RS_Score_Raw: 6.62172 (applicability domain score: 0.855388) -RSCONVOL_Score_Raw: 7.56154 (applicability domain score: 0.987362) - -Property Predictions -XLogP: 2.23575 -XLogS: -5.67178 -XdG_Hyd: -11.4231 -MoleculeComplexity: 0.987633 - -Additional Properties -Weight: 431.91 -Number of rotatable bonds: 8 -TPSA: 78.94 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -13.035 (REU) -RS_Score_Raw: 5.86903 (applicability domain score: 0.148076) -RSCONVOL_Score_Raw: 7.44022 (applicability domain score: 0.988751) - -Property Predictions -XLogP: 2.30494 -XLogS: -7.03307 -XdG_Hyd: -11.0492 -MoleculeComplexity: 1.08784 - -Additional Properties -Weight: 480.93 -Number of rotatable bonds: 9 -TPSA: 66.05 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 5 - :Activity Predictions -RosettaLigandInterfaceScore: -14.822 (REU) -RS_Score_Raw: 7.15778 (applicability domain score: 0.801316) -RSCONVOL_Score_Raw: 7.56646 (applicability domain score: 0.983748) - -Property Predictions -XLogP: 2.40799 -XLogS: -6.711 -XdG_Hyd: -10.9846 -MoleculeComplexity: 1.01254 - -Additional Properties -Weight: 447.37 -Number of rotatable bonds: 8 -TPSA: 66.05 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 5 - :Activity Predictions -RosettaLigandInterfaceScore: -12.448 (REU) -RS_Score_Raw: 5.25659 (applicability domain score: 0.246124) -RSCONVOL_Score_Raw: 6.29705 (applicability domain score: 0.986911) - -Property Predictions -XLogP: 1.92285 -XLogS: -4.68398 -XdG_Hyd: -11.3429 -MoleculeComplexity: 0.962834 - -Additional Properties -Weight: 392.9 -Number of rotatable bonds: 8 -TPSA: 83.12 -Number of hydrogen bond donors: 3 -Number of hydrogen bond acceptors: 6 - :Activity Predictions -RosettaLigandInterfaceScore: -11.284 (REU) -RS_Score_Raw: 5.72722 (applicability domain score: 0.300933) -RSCONVOL_Score_Raw: 6.34584 (applicability domain score: 0.98544) - -Property Predictions -XLogP: 2.68415 -XLogS: -4.71846 -XdG_Hyd: -9.52979 -MoleculeComplexity: 0.938138 - -Additional Properties -Weight: 393.88 -Number of rotatable bonds: 8 -TPSA: 80.32 -Number of hydrogen bond donors: 2 -Number of hydrogen bond acceptors: 6 -

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