3D-QSAR Study of Melanin Inhibiting (S)-(+)-Decursin Bull. Korean Chem. Soc. 2012, Vol. 33, No. 1 149 http://dx.doi.org/10.5012/bkcs.2012.33.1.149 3D-QSAR Study of Melanin Inhibiting (S)-(+)-Decursin and its Analogues by Pharmacophore Mapping Kyeong Lee, a Sang Won Jung, †,a Ravi Naik, and Art E. Cho †,* College of pharmacy, Dongguk University-Seoul, Seoul 100-715, Korea † Department of Bioinformatics, Korea University, Yeongi-gun, Chungnam 339-700, Korea. * E-mail: artcho@korea.ac.kr Received September 30, 2011, Accepted November 15, 2011 The (S)-(+)-decursin and its analogues are reported as potent inhibitors of melanin production in B16 murine melanoma cells. In order to understand the factors responsible for potency as well as inhibition of potency of (S)-(+)-decursin and its analogues, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed. Since receptor structures are not available, a pharmacophore model was constructed. Using PHASE, we generated 3 different models and selected the seven-site model, which returned excellent statistical values (r 2 = 0.9127, Q 2 = 0.6878, Pearson-R = 0.9014). Using the generated pharmacophore model, we screened a natural products library and obtained 4'-epi-decursin as the most related compound. 4'-epi- decursin is similar to (S)-(+)-decursin, but shows additional interaction possibilities with tyrosinase. The study thus sheds some light on possibility of developing more potent tyrosinase inhibitors. Key Words : Pharmacophore, (S)-(+)-Decursin, Melanin inhibitors, 3D-QSAR, PHASE Introduction Melanosomes are intracellular membrane-bound organelles within which melanin’s are synthesized and stored in specialized pigment cells, including melanocytes and retinal and iris pigment epithelial cells. 1 Melanin plays a very important role in protecting human skin from the noxious effects of sunlight, toxic drugs and various chemicals. 2 How- ever, hyper-pigmentation of the skin is a common problem that is prevalent in middle aged and elderly people. It is caused by over production of melanin inside the body. Tyrosine enzyme is known to be the key enzyme in melanin production. 3,19 Increased levels of melanin production known to cause diverse hyper-pigmentary disorders such as melasma, freckles, age sports and actinic damage, which result in the accumulation of increased levels of epidermal and dermal pigmentation. Thus therapeutic means for the treatment of dermatological disorders and the development of cosmetic whitening agent can be achieved by means of inhibition of abnormal deposition of melanin. 2,4-6 The (S)-(+)-decursin and its analogues are novel candi- dates for cancer treatment as well, which are isolated from Angelica gigasNakai plant and were known to exhibit wide range of biological properties. We reported that these ana- logues were found to be potent inhibitors of melanin pro- duction in B16 melanoma cells. In order to understand the factors affecting the activity of (S)-(+)-decursin as potent inhibitor of melanin production, three-dimensional-quanti- tative structure-activity relationship (3D-QSAR) studies were performed. 3D-QSAR methods have been developed to visually examine the steric and electrostatic fields surround- ing binding sites. It requires three-dimensional structures to calculate energies. For this purpose, we used PHASE pro- gram of Schrödinger suite to generate pharmacophore models. 2,7 Materials and Methods Data Sets. A set of 33, (S)-(+)-decursin and its analogues as potent inhibitors of melanin formation, from our previ- ously published work, was used for pharmacophore gene- ration. In the previous work, the biological activities of these compounds were measured as inhibition rate at 100 μM and we converted these values to IC 50 assuming linear relation around the data points. 2 It is a reasonable assumption given that most of the measured inhibition rates hover about 50%. These converted values, along with their negative logarithms that were eventually used in our 3D-QSAR study, are tabulated in Table 1. Preparation of Ligands. Structures of the compounds were generated by 2D sketcher and LigPrep module of Schrödinger. 14 Conformers for each ligand were generated using Mixed MCMM/LMOD method with OPLS-2005 force field and implicit distance-dependent dielectric solvent model at cutoff root mean square deviation (RMSD) of 1 Å. For each molecule, conformers with the maximum energy difference of 30 kcal/mol relative to the global energy minimum conformer were obtained. Generation of Common Pharmacophore Hypothesis. Common pharmacophore hypothesis (CPH) was generated using PHASE from Schrödinger. 16,17 Pharmacophore features - hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic group (H), and aromatic ring (R) - were defined by a set of chemical structure patterns by PHASE. PHASE assigns features one of the three possible geometries - point, vector, or group - which define physical characteristic of the a These authors contributed equally to this work.