In silico modeling of functionalized poly(methylvinyl ether/maleic acid) for controlled drug release in the ocular milieu.

Controlling structurally defined properties of drug-bound macromolecules such as surface adhesion and interaction with endogenous proteins in the surrounding environment using prior data from computer-assisted simulation can be of great use in designing controlled release macromolecular therapeutic systems. In this paper, we describe experimental correlation of real-time properties of a polymer with pendant drug molecules, with predicted values obtained from studying in silico molecular interactions of this polymer with ocular surface proteins (mucin) for formulating an ophthalmic in situ gel. Mucoretention of the drug (norfloxacin) within the eye sac is closely associated with binding interactions occurring on the ocular surface, and covalent association of the drug with the mucoadhesive polymer, poly(methylvinyl ether/maleic acid), can largely reduce dosing frequency eliciting prolonged antibacterial action much required in treating conjunctival infections. The physicochemical properties and 3D conformation of the drug-polymer conjugate were predicted by computational studies. Molecular docking of the drug-polymer conjugate with ocular surface mucin (MUC-1) suggested that amino acid residues Arg1095, Asn1091, and Gln1070 of mucin are involved in hydrogen bonding with carboxyl residues in the polymer structure. The orientation of the drug-polymer conjugate in solution profoundly depends on the properties of the drug. The studies further reveal that molecular interactions of MUC-1 with the drug in the drug-polymer conjugate influence the binding orientation of the drug-polymer to mucin. Computationally predicted solvation energies revealed a significant difference in energy values between drug molecule alone (- 113.04 kcal/mol) and the drug-polymer (- 492.44 kcal/mol) suggesting higher aqueous solvation of the drug-polymer conjugate compared with less-soluble drug, and that interactions between polymer chains and ocular aqueous environment dictate the drug-polymer conjugate's free energy. Our results demonstrate the fabrication of a macromolecular therapeutic gel using drug-polymer with controlled release properties and mucoadhesion guided by information predicted from computational software. Notably, in silico studies reveal that even small variations in molecular composition, in this case, an antibacterial drug that contributes less than half of the entire molecular weight can considerably change the drug's presentation to the ocular environment. Graphical abstract Table of contents graphic.