Insilico discovery of novel Phosphodiesterase 4 (PDE4) inhibitors for the treatment of psoriasis: Insights from computer aided drug design approaches

• Published in: PloS one Vol. 19; no. 11; p. e0305934
• Main Authors: Alanzi, Abdullah R, Alsalhi, Mohammed S, Mothana, Ramzi A, Alqahtani, Jawaher H, Alqahtani, Moneerah J
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 01.11.2024
• Subjects: Affinity; Binding; Biological activity; Biological effects; Biology and Life Sciences; CAD; Chronic obstructive pulmonary disease; Comorbidity; Computer aided design; Cytokines; Drug development; Enzymes; Hydrogen bonds; Hypotheses; Immune system; Inflammatory diseases; Inhibitors; Kinases; Ligands; Medicine and Health Sciences; Molecular docking; Pathogenesis; Permeability; Phosphodiesterase; Phosphodiesterase IV; Physical Sciences; Proteins; Psoriasis; Psoriatic arthritis; Research and Analysis Methods; Screening; Simulation; Skin diseases; Stability analysis; Steroids; Therapeutic targets; Toxicity; Tumor necrosis factor-TNF
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0305934

Psoriasis is chronic immune-mediated inflammatory disorder characterized by various comorbidities, erythematous plaques with silvery scale which can lead to psoriatic arthritis. The phosphodiesterase 4 (PDE4) protein is a potential drug target to control Psoriasis. In the current study, pharmacophore-based virtual screening of Diversity library of ChemDiv database was first performed, and then the screened hits were docked to the active site of PDE4 to choose the best binding modes. Forty-six hits generated during the virtual screening were prepared and docked to the PDE4 receptor by SP docking module of glide. The binding affinities of the selected hits were calculated by molecular docking and based on the affinities, ten hits were selected for the bioactivity scores prediction and ADMET analysis. Based on the ADMET profiling, four hits D356-2630, C700-2058, G842-0420 and F403-0203 were processed to MD simulations for stability analysis. The outcomes showed that these compounds showed strong binding with proteins with better binding free energies. Based on the results of our study, we proposed that these hits can function as lead in the biological assays and in vitro studies are required to develop the novel drug candidates.