Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds

Frontiers in Chemistry

Andrés González Barrios²  Alejandro Reyes Muñoz³  Andrés Felipe Vásquez⁴  Jorge Duitama⁵ 

[1] Grupo de Biología Computacional y Ecología Microbiana (BCEM), Department of Biological Sciences, Universidad de Los Andes, Bogotá, Colombia;Grupo de Diseño de Productos y Procesos (GDPP), Department of Chemical Engineering, Universidad de Los Andes, Bogotá, Colombia;Max Planck Tandem Group in Computational Biology, Universidad de Los Andes, Bogotá, Colombia;Naturalius S.A.S, Bogotá, Colombia;Systems and Computing Engineering Department, Universidad de Los Andes, Bogotá, Colombia;

关键词: fragment-based drug discovery;    RECAP;    virtual screening;    pharmacophore modeling;    property-based design;    protein-ligand interactions;   

DOI  :  10.3389/fchem.2021.700802

来源: DOAJ

【 摘 要 】

Fragment-based drug design (FBDD) and pharmacophore modeling have proven to be efficient tools to discover novel drugs. However, these approaches may become limited if the collection of fragments is highly repetitive, poorly diverse, or excessively simple. In this article, combining pharmacophore modeling and a non-classical type of fragmentation (herein called non-extensive) to screen a natural product (NP) library may provide fragments predicted as potent, diverse, and developable. Initially, we applied retrosynthetic combinatorial analysis procedure (RECAP) rules in two versions, extensive and non-extensive, in order to deconstruct a virtual library of NPs formed by the databases Traditional Chinese Medicine (TCM), AfroDb (African Medicinal Plants database), NuBBE (Nuclei of Bioassays, Biosynthesis, and Ecophysiology of Natural Products), and UEFS (Universidade Estadual de Feira de Santana). We then developed a virtual screening (VS) using two groups of natural-product-derived fragments (extensive and non-extensive NPDFs) and two overlapping pharmacophore models for each of 20 different proteins of therapeutic interest. Molecular weight, lipophilicity, and molecular complexity were estimated and compared for both types of NPDFs (and their original NPs) before and after the VS proceedings. As a result, we found that non-extensive NPDFs exhibited a much higher number of chemical entities compared to extensive NPDFs (45,355 vs. 11,525 compounds), accounting for the larger part of the hits recovered and being far less repetitive than extensive NPDFs. The structural diversity of both types of NPDFs and the NPs was shown to diminish slightly after VS procedures. Finally, and most interestingly, the pharmacophore fit score of the non-extensive NPDFs proved to be not only higher, on average, than extensive NPDFs (56% of cases) but also higher than their original NPs (69% of cases) when all of them were also recognized as hits after the VS. The findings obtained in this study indicated that the proposed cascade approach was useful to enhance the probability of identifying innovative chemical scaffolds, which deserve further development to become drug-sized candidate compounds. We consider that the knowledge about the deconstruction degree required to produce NPDFs of interest represents a good starting point for eventual synthesis, characterization, and biological activity studies.

【 授权许可】

Unknown