Molecular Modeling of Drug-Albumin Interactions: A case Study on Antifungal Agents

Background & objectives: the interaction of albuminthe most important plasma proteinwith various drugs leads to variations in the pharmacokinetics of drugs. Since interaction of different pharmaceuticals with albumin is determinant in the estimation of dose and prediction of drug-drug and drug-food interferences, studying the binding ability of different drugs with albumin is an active area of research. Methods: Docking studies were performed by Lamarckian Genetic Algorithm of AutoDock 4.2 program. The three-dimensional structures of albumin were obtained from Brookhaven protein data bank (2BXD & 2BXF; www.rcsb.org). Pre-processing of molecules was done using AM1 method and AutoDock Tools 1.5.4 software. AM1 optimization method was performed using Polak-Ribiere (conjugate gradient) algorithm with termination condition as RMS gradient of 0.1 Kcal/Å mol. Schematic representation of drug-albumin complexes were obtained by Ligplot. Results: Oxiconazole and fenticonazole were top-ranked drugs in binding to site 1 (subdomain IIA) and 2 (subdomain IIIA) of albumin, respectively (∆Gb -9.01 and -9.89 kcal.mol). Leu238 and Ala291 were the key residues of site 1 due to hydrophobic contacts with all of the antifungals, while Ile388, Asn391 and Leu430 were the key residues of site 2. A few structure binding relationship rules could be extracted from the binding pattern of antifungal drugs. Conclusion: It was found that antifungal agents might have higher affinity toward site 2 of albumin rather than site 1. Estimated high albumin affinities of antifungals provided the possibility of drug-drug or drug-food interactions. It seemed that hydrophobic contacts were more significant in binding antifungals to albumin.