ABFE, absolute binding free energy; BAR, Bennet acceptance ratio; Binding potencies; DCM, dichloromethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; Drug discovery; FEP, free energy perturbation; Free energy perturbation; GAFF, general AMBER force field; HPLC, high performance liquid chromatography; HRMS, High resolution mass spectra; IC50, half-inhibitory concentration; IPTG, isopropyl b-d-thiogalactopyranoside; LV, left ventricle; MAD, mean absolute deviations; MD, molecular dynamics; MM-GBSA, molecular mechanics/generalized born surface area; Molecular design; PAH, pulmonary arterial hypertension; PDB, protein data bank; PDE, phosphodiesterase; PDE5 inhibitors; PDE5, phosphodiesterase-5; PME, particle mesh Ewald; Privileged scaffolds; Pulmonary arterial hypertension; RBFE, relative binding free energy; RED, restraint energy distribution; RESP, restrained electrostatic potential; RV, right ventricle; RVHI, right ventricle hypertrophy index; SARs, structure­activity relationships; Scaffold hopping; THF, tetrahydrofuran; TLC, thin-layer chromatography; WT, wall thickness; ip, intraperitoneal injection; iv, intravenous administration; mPAP, pulmonary artery pressure; po, oral administration (per os)