BioisoIdentifier: an online free tool to investigate local structural replacements from PDB

Abstract

Abstract Within the realm of contemporary medicinal chemistry, bioisosteres are empirically used to enhance potency and selectivity, improve adsorption, distribution, metabolism, excretion and toxicity profiles of drug candidates. It is believed that bioisosteric know-how may help bypass granted patents or generate novel intellectual property for commercialization. Beside the synthetic expertise, the drug discovery process also depends on efficient in silico tools. We hereby present BioisoIdentifier (BII), a web server aiming to uncover bioisosteric information for specific fragment. Using the Protein Data Bank as source, and specific substructures that the user attempt to surrogate as input, BII tries to find suitable fragments that fit well within the local protein active site. BII is a powerful computational tool that offers the ligand design ideas for bioisosteric replacing. For the validation of BII, catechol is conceived as model fragment attempted to be replaced, and many ideas are successfully offered. These outputs are hierarchically grouped according to structural similarity, and clustered based on unsupervised machine learning algorithms. In summary, we constructed a user-friendly interface to enable the viewing of top-ranking molecules for further experimental exploration. This makes BII a highly valuable tool for drug discovery. The BII web server is freely available to researchers and can be accessed at http://www.aifordrugs.cn/index/ . Scientific Contribution: By designing a more optimal computational process for mining bioisosteric replacements from the publicly accessible PDB database, then deployed on a web server for throughly free access for researchers. Additionally, machine learning methods are applied to cluster the bioisosteric replacements searched by the platform, making a scientific contribution to facilitate chemists’ selection of appropriate bioisosteric replacements. The number of bioisosteric replacements obtained using BII is significantly larger than the currently available platforms, which expanding the search space for effective local structural replacements. Graphical Abstract