STRUCTURAL AND FUNCTIONAL CONSEQUENCES OF PTGER3 VARIANTS ASSOCIATED WITH CONJUNCTIVITIS: A BIOINFORMATICS APPROACH

Abstract

Conjunctivitis (pink eye) remains a prevalent ocular condition, with Pakistan reporting ~400,000 cases in 2023, particularly in Punjab. While infectious agents are the primary drivers, host genetic factors may modulate individual susceptibility. Prostaglandin E receptor 3 (PTGER3), encoded on chromosome 1p31.1, plays a central role in PGE₂‐mediated inflammatory signaling. In this study, we present the first in silico analysis of PTGER3 single‐nucleotide polymorphisms (SNPs) linked to conjunctival inflammation. Out of 27,077 SNPs retrieved from the NCBI and gnomAD databases, preliminary screening via SIFT and PolyPhen identified 51 potentially deleterious variants. Consensus analysis using 10 different bioinformatics tools further refined the list to 15 high-risk SNPs. Structural assessments by the HOPE server highlighted mutations such as C358R, E279K, and T277M, which significantly affect side-chain geometry and protein core stability. Wild-type and mutant models were constructed based on the AlphaFold-derived PE2R3_HUMAN (P43115A) structure and validated for stereochemical quality. FTSite analysis predicted key ligand-binding pockets, notably involving residues ALA148, LEU145, ILE287, THR138, and LEU299. Molecular docking was executed in PyRx using AutoDock Vina for both blind and focused searches. A panel of 12 anti-infective and anti-inflammatory compounds, including Luteolin, G-Mangostin, Ganomycin-I, and Proflavine, was docked against the wild-type and mutant PTGER3 proteins. Notably, strong binding affinities and interactions were observed for Luteolin, G-Mangostin, and Proflavine in the wild-type, while T277M, E279K, and C358R mutants displayed altered interaction profiles. The docking simulations, visualized through Discovery Studio Biovia, revealed critical hydrogen bonds and hydrophobic contacts stabilizing the ligand–protein complexes. These findings underscore the structural vulnerability of PTGER3 to specific amino acid substitutions and highlight several promising compounds for further evaluation as targeted EP3 receptor modulators in conjunctivitis treatment approaches.