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114th General Meeting of Korean Chemical Society Structure ensemble based virtual screening discovered new inhibitors of tyrosinase

Submission Date :
8 / 28 / 2014 , 15 : 29 : 46
Abstract Number :
Presenting Type:
Poster Presentation
Presenting Area :
Authors :
최준혁, 지준구*
경북대학교 약학과, Korea
Assigned Code :
BIO.P-633 Assigend Code Guideline
Presenting Time :
10월 15일 (수요일) 16:00~19:00
Tyrosinase participates in two distinct reactions, the hydroxylation of L-Tyrosine to L-DOPA and the subsequent conversion of L-DOPA to L-Dopaquinone, in producing melanin in melanocyte. Central roles of melanin in melanocyte have attracted attentions from pharmaceutical and cosmetic companies for developing therapeutic and cosmetic agents by inhibiting the function of tyrosinase. Here we report new inhibitors of mushroom tyrosinase that were predicted by computational methods and confirmed by enzymatic and biophysical assays. In order to enhance the performance of virtual screening, molecular dynamics simulation first produced an ensemble of 10,000 trajectories. Second, we chose a structure that revealed the optimal receiver operating characteristic curve with the known direct binders and their physicochemically matched decoys. Third, high-throughput virtual screening was performed against small molecule library that consists of about 400,000 commercially available molecules. Fourth, we purchased top 60 molecules and tested their inhibitory activities. The extended assays with the analogues of the molecules that showed activities followed. In total, about 30 new inhibitors of tyrosinase were discovered. Several compounds showed much stronger activities than the known tyrosinase inhibitors of arbutin, hydroquinone and kojic acid, having IC50 values in nM range.