Konc Janez, Lešnik Samo, Škrlj Blaž, Sova Matej, Proj Matic, Knez Damijan, Gobec Stanislav, Janežič Dušanka
National Institute of Chemistry, Theory Department, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
Jozef Stefan International Postgraduate School, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
J Chem Inf Model. 2022 Mar 28;62(6):1573-1584. doi: 10.1021/acs.jcim.1c01176. Epub 2022 Mar 15.
The protein data bank (PDB) is a rich source of protein ligand structures, but ligands are not explicitly used in current docking algorithms. We have developed ProBiS-Dock, a docking algorithm complementary to the ProBiS-Dock Database ( 4097-4107) that treats small molecules and proteins as fully flexible entities and allows conformational changes in both after ligand binding. A new scoring function is described that consists of a binding site-specific scoring function (ProBiS-Score) and a general statistical scoring function. ProBiS-Dock enables rapid docking of small molecules to proteins and has been successfully validated in silico against standard benchmarks. It enables rapid search for new active ligands by leveraging existing knowledge in the PDB. The potential of the software for drug development has been confirmed in vitro by the discovery of new inhibitors of human indoleamine 2,3-dioxygenase 1, an enzyme that is an attractive target for cancer therapy and catalyzes the first rate-determining step of l-tryptophan metabolism via the kynurenine pathway. The software is freely available to academic users at http://insilab.org/probisdock.
蛋白质数据库（PDB）是蛋白质配体结构的丰富来源，但目前的对接算法并未明确使用配体。我们开发了ProBiS-Dock，这是一种与ProBiS-Dock数据库（4097 - 4107）互补的对接算法，它将小分子和蛋白质视为完全灵活的实体，并允许在配体结合后两者都发生构象变化。描述了一种新的评分函数，它由结合位点特异性评分函数（ProBiS-Score）和通用统计评分函数组成。ProBiS-Dock能够实现小分子与蛋白质的快速对接，并已在计算机模拟中针对标准基准成功验证。它通过利用PDB中的现有知识，能够快速搜索新的活性配体。通过发现人类吲哚胺2,3-双加氧酶1的新抑制剂，该软件在药物开发方面的潜力已在体外得到证实，吲哚胺2,3-双加氧酶1是一种对癌症治疗有吸引力的靶点，催化色氨酸通过犬尿氨酸途径代谢的第一个限速步骤。学术用户可在http://insilab.org/probisdock免费获取该软件。
