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Computational methods-guided design of modulators targeting protein-protein interactions (PPIs).

Abstract：

:Protein-protein interactions (PPIs) play a pivotal role in extensive biological processes and are thus crucial to human health and the development of disease states. Due to their critical implications, PPIs have been spotlighted as promising drug targets of broad-spectrum therapeutic interests. However, owing to the general properties of PPIs, such as flat surfaces, featureless conformations, difficult topologies, and shallow pockets, previous attempts were faced with serious obstacles when targeting PPIs and almost portrayed them as "intractable" for decades. To date, rapid progress in computational chemistry and structural biology methods has promoted the exploitation of PPIs in drug discovery. These techniques boost their cost-effective and high-throughput traits, and enable the study of dynamic PPI interfaces. Thus, computational methods represent an alternative strategy to target "undruggable" PPI interfaces and have attracted intense pharmaceutical interest in recent years, as exemplified by the accumulating number of successful cases. In this review, we first introduce a diverse set of computational methods used to design PPI modulators. Herein, we focus on the recent progress in computational strategies and provide a comprehensive overview covering various methodologies. Importantly, a list of recently-reported successful examples is highlighted to verify the feasibility of these computational approaches. Finally, we conclude the general role of computational methods in targeting PPIs, and also discuss future perspectives on the development of such aids.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Qiu Y,Li X,He X,Pu J,Zhang J,Lu S

doi

10.1016/j.ejmech.2020.112764

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

112764

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30736-4

journal_volume

207

pub_type

杂志文章,评审

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