Table 3.

Summary of the intermolecular binding energetics of human plasma kallikrein complexes with DON and DRP-104 in relation to the reference drug, berotralstat, and phase 3 inhibitor sebetralstat, expressed in kcal/mol with standard deviations. Binding calculations were performed using the MMGBSA method with 200000 frames

Intermolecular binding energy units (kcal/mol)	Human plasma kallikrein-ligand complex
	PKa-DON	PKa-DRP-104	PKa–Berotralstat	PKa–Sebetralstat
∆EvdW	−23.27 ± 2.67	−41.44 ± 4.32	−45.42 ± 4.28	−63.87 ± 3.35
∆Eelec	−16.48 ± 11.19	8.25 ± 17.69	43.51 ± 29.43	−39.60 ± 8.65
∆GGB	24.68 ± 9.20	7.86 ± 15.57	−23.61 ± 27.01	58.31 ± 7.57
∆GSA	−3.51 ± 0.13	−5.30 ± 0.50	−5.90 ± 0.46	−6.81 ± 0.28
∆Ggas	−39.75 ± 10.36	−33.19 ± 17.67	−1.91 ± 29.66	−103.47 ± 9.36
∆Gsolv	21.17 ± 9.22	2.58 ± 15.44	−29.50 ± 26.83	51.50 ± 7.41
∆Gbind	−18.58 ± 3.57	−30.62 ± 4.75	−31.41 ± 4.97	−51.97 ± 3.66

∆E_elec (electrostatic energy), ∆E_vdW (van der Waals energy), ∆G_bind (total free binding energy) ∆G_gas (gas-phase energy), ∆G_GB (polar solvation energy), ∆G_SA (non-polar solvation energy), and ∆G_solv (Total solvation free energy of polar and non-polar states)