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

Background & objectives: the interaction of albumin- the most important plasma protein- with 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-1). 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. &nbsp