1130 Clinically relevant differences in the chemical and structural mechanism of action of dermatological phosphodiesterase-4 inhibitors

The United States Food and Drug Administration recently approved the third dermatological phosphodiesterase-4 (PDE4) inhibitor, roflumilast, for topical treatment of psoriasis. It is more potent effective than its two predecessors, apremilast crisaborole. All 3 are rationally designed PDE4 inhibitors with in vitro inhibitory constant IC50 of: 0.14 μM (apremilast), 0.24 (crisaborole), 0.7 nM (roflumilast). molecular mechanism explaining why roflumilast inhibits better or crisaborole has not been elucidated. a 3',5'-cyclic adenosine monophosphate (cAMP) hydrolase consisting at least 4 subtypes exon-spliced isoforms, which primarily expressed immune cells inflammatory response. inhibition bursts cellular cAMP concentrations, generating anti-inflammatory effects. Initially studied chronic obstructive pulmonary disease, have emerged as psoriasis atopic dermatitis therapies. Using structural computational biology techniques, we examined in-depth physicochemical principles that (i) make (ii) distinguish mechanistically. Sequence alignment catalytic domains all PDEs identified several new invariant amino acids critical to action: these residues bind one Zn2+ Mg2+ ion plus five structured water molecules orienting an attacking μ-hydroxyl/μ-oxo anion stabilizing non-bridging phosphate oxygen atoms. arrangement divalent metal ions related classic general phosphoryl transfer, contrast HIV integrase. These findings establish chemical basis roflumilast’s affinity PDE4, identify key differences hydrogen bonding, ligand coordination, hydrophobic interactions between crisaborole, direct next-generation inhibitor design.