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FragPELE: Dynamic Ligand Growing within a Binding Site. A Novel Tool for Hit-To-Lead Drug Design.

Abstract：

:The early stages of drug discovery rely on hit-to-lead programs, where initial hits undergo partial optimization to improve binding affinities for their biological target. This is an expensive and time-consuming process, requiring multiple iterations of trial and error designs, an ideal scenario for applying computer simulation. However, most state-of-the-art modeling techniques fail to provide a fast and reliable answer to the Induced-Fit protein-ligand problem. To aid in this matter, we present FragPELE, a new tool for in silico hit-to-lead drug design, capable of growing a fragment from a bound core while exploring the protein-ligand conformational space. We tested the ability of FragPELE to predict crystallographic data, even in cases where cryptic sub-pockets open because of the presence of particular R-groups. Additionally, we evaluated the potential of the software on growing and scoring five congeneric series from the 2015 FEP+ dataset, comparing them to FEP+, SP and Induced-Fit Glide, and MMGBSA simulations. Results show that FragPELE could be useful not only for finding new cavities and novel binding modes in cases where standard docking tools cannot but also to rank ligand activities in a reasonable amount of time and with acceptable precision.

journal_name

J Chem Inf Model

journal_title

Journal of chemical information and modeling

authors

Perez C,Soler D,Soliva R,Guallar V

doi

10.1021/acs.jcim.9b00938

subject

Has Abstract

pub_date

2020-03-23 00:00:00

pages

1728-1736

issue

3

eissn

1549-9596

issn

1549-960X

journal_volume

60

pub_type

杂志文章

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