Vinkers H Maarten, de Jonge Marc R, Daeyaert Frederik F D, Heeres Jan, Koymans Lucien M H, van Lenthe Joop H, Lewi Paul J, Timmerman Henk, Van Aken Koen, Janssen Paul A J
Center for Molecular Design, Janssen Pharmaceutica N.V., Antwerpsesteenweg 37, B-2350 Vosselaar, Belgium.
J Med Chem. 2003 Jun 19;46(13):2765-73. doi: 10.1021/jm030809x.
We present a de novo design program called SYNOPSIS, that includes a synthesis route for each generated molecule. SYNOPSIS designs novel molecules by starting from a database of available molecules and simulating organic synthesis steps. This way of generating molecules imposes synthetic accessibility on the molecules. In addition to a starting database, a fitness function is needed that calculates the value of a desired property for an arbitrary molecule. The values obtained from this function guide the design process in optimizing the molecules toward an optimal value of the calculated property. Two applications are described. The first uses an electric dipole moment calculation to generate molecules possessing a strong dipole moment. The second makes use of the three-dimensional structure of a viral enzyme in order to generate high affinity ligands. Twenty eight compounds designed with the program resulted in 18 synthesized and tested compounds, 10 of which showed HIV inhibitory activity in vitro.
我们提出了一个名为SYNOPSIS的全新设计程序，它为每个生成的分子都包含一条合成路线。SYNOPSIS通过从可用分子数据库出发并模拟有机合成步骤来设计新型分子。这种生成分子的方式使分子具有合成可及性。除了起始数据库外，还需要一个适应度函数，该函数能为任意分子计算所需性质的值。从该函数获得的值在优化分子以使其朝着计算性质的最优值发展的过程中指导设计过程。文中描述了两个应用。第一个应用利用电偶极矩计算来生成具有强偶极矩的分子。第二个应用利用病毒酶的三维结构来生成高亲和力配体。用该程序设计的28种化合物中有18种被合成并进行了测试，其中10种在体外显示出HIV抑制活性。
