Characterization of AfroDb Chemical Library

The previously prepared 1,008 low energy 3D chemical structures in the AfroDb library were saved in.mol2 format and initially treated with LigPrep [63] , distributed by Schrodinger Inc. This implementation was carried out with the graphical user interface (GUI) of the Maestro software package [64] , using the OPLS forcefield [65] (link)–[67] (link). Protonation states at biologically relevant pH were correctly assigned (group I metals in simple salts were disconnected, strong acids were deprotonated, strong bases protonated, while topological duplicates and explicit hydrogens were added). A set of ADMET-related properties (a total of 46 molecular descriptors) were calculated by using the QikProp program [68] running in normal mode. QikProp generates physically relevant descriptors, and uses them to perform ADMET predictions. An overall ADME-compliance score – drug-likeness parameter (indicated by #stars), was used to assess the pharmacokinetic profiles of the compounds within the AfroDb library. The #stars parameter indicates the number of property descriptors computed by QikProp that fall outside the optimum range of values for 95% of known drugs. The methods implemented were developed by Jorgensen et al. [69] (link)–[70] and among the calculated descriptors are: the total solvent-accessible molecular surface, in Ų (probe radius 1.4 Å) (range for 95% of drugs: 300–1000 Ų); the hydrophobic portion of the solvent-accessible molecular surface, in Ų (probe radius 1.4 Å) (range for 95% of drugs: 0–750 Ų); the total volume of molecule enclosed by solvent-accessible molecular surface, in ų (probe radius 1.4 Å) (range for 95% of drugs: 500–2000 ų); the logarithm of aqueous solubility, (range for 95% of drugs: −6.0 to 0.5) [69] (link), [71] (link); the logarithm of predicted binding constant to human serum albumin, (range for 95% of drugs: −1.5 to 1.2) [72] (link); the logarithm of predicted blood/brain barrier partition coefficient, logB/B (range for 95% of drugs: −3.0 to 1.0) [73] (link)–[75] (link); the predicted apparent Caco-2 cell membrane permeability (BIP_caco-2) in Boehringer–Ingelheim scale, in nm/s (range for 95% of drugs: <5 low, >100 high) [76] (link)–[78] (link); the predicted apparent Madin-Darby canine kidney (MDCK) cell permeability in nm s⁻¹ (<25 poor, >500 great) [77] (link); the index of cohesion interaction in solids, Ind_coh, calculated from the HBA, HBD and the surface area accessible to the solvent, SASA ( ) by the relation Ind_coh = HBA HBD^1/2/ (0.0 to 0.05 for 95% of drugs) [71] (link); the globularity descriptor, Glob =  , where r is the radius of the sphere whose volume is equal to the molecular volume (0.75 to 0.95 for 95% of drugs); the predicted polarizability, (13.0 to 70.0 for 95% of drugs); the predicted logarithm of IC₅₀ value for blockage of HERG K⁺ channels, logHERG (concern<−5) [79] (link)–[80] (link); the predicted skin permeability, (−8.0 to −1.0 for 95% of drugs) [81] (link)–[82] (link); and the number of likely metabolic reactions, #metab (range for 95% of drugs: 1–8).