Computer-aided drug design in new druggable targets for the next generation of immune-oncology therapies

Rita C. Acúrcio, Anna Scomparin, Ronit Satchi-Fainaro, Helena F. Florindo*, Rita C. Guedes

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Immune modulatory pathways have emerged as innovative and successful targets in cancer immunotherapy. Current therapeutics include monoclonal antibodies, which have shown impressive clinical results in the treatment of several types of tumors. However, the failure to show response in the majority of patients and the induction of severe immune-related adverse effects are among the major drawbacks. Latest efforts to achieve new approaches to target additional pathways and/or protein responsible for immune evasion toward the development of immune modulatory small molecules have been devised. The potential of innovative computational-aided drug design tools to accelerate the identification and design of new optimized and validated immune small molecules modulators will play a key role in the next generation of cancer immunotherapy drug discovery. Nevertheless, the lack of structural information regarding the immune modulatory pathways and other components within tumor microenvironment has hampered the rational design of those small-molecule modulators, by preventing the use of such methodologies. Herein we provide an overview on structural elucidation on known regulators of immune modulatory pathways (adenosine A 2A receptor [A 2A R], stimulator of interferon genes [STING], indoleaine 2,3-dioxygenase 1 [IDO1], and 4-1BB) within cancer microenvironment. This knowledge on immune modulatory molecular targets is essential to advance the understanding of their binding mode and guide the design of novel effective targeted anticancer medicines. This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods Structure and Mechanism > Molecular Structures Software > Molecular Modeling.

Original languageEnglish
Article numbere1397
JournalWiley Interdisciplinary Reviews: Computational Molecular Science
Issue number3
StatePublished - 1 May 2019


FundersFunder number
Ci?ncia e a Tecnologia
FCT-MCTESENMed/0051/2016, PD/BD/128238/2016
Fundação para a Ciência e a TecnologiaUID/DTP/04138/2013, PTDC/QEQ-MED/7042/2014, SAICTPAC/0019/2015
Ministério da Ciência, Tecnologia e Ensino SuperiorPD/BD/128238/2016RA
Ministry of Health, State of Israel
Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção
Programa Operacional Temático Factores de Competitividade


    • 4-1BB
    • A R
    • IDO1
    • STING
    • computational-aided drug design
    • immune checkpoint receptors
    • tumor microenvironment


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