Carbamate and <i>N</i>-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors

Li, Derun; Deng, Yongqi; Achab, Abdelghani; Bharathan, Indu; Hopkins, Brett A.; Yu, Wei; Zhang, Hongjun; Sanyal, Sulagna; Pu, Qinglin; Zhou, Hua; Liu, Kun; Lim, Jongwon; Fradera, Xavier; Lesburg, Charles A.; Lammens, Alfred; Martinot, Theodore A.; Cohen, Ryan D.; Doty, Amy; Ferguson, Heidi; Nickbarg, Elliott; Cheng, Mangeng; Spacciapoli, Peter; Geda, Prasanthi; Song, Xuelei S.; Smotrov, Nadya; Abeywickrema, Pravien; Andrews, Christine L.; Chamberlin, Chad; Mabrouk, Omar S.; Curran, Patrick J.; Richards, Matthew P.; Saradjian, P; Miller, J. Richard; Knemeyer, Ian; Otte, Karin; Vincent, Stella; Sciammetta, Nunzio; Pasternak, Alexander; Bennett, David Jonathan; Han, Yongxin

doi:10.1021/acsmedchemlett.0c00525

Cited by 18 publications

(22 citation statements)

References 34 publications

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“…[8][9][10] In particular, overexpression of hIDO1 by cancer cells has been shown to induce immune escape and resistance to immunotherapy [11][12][13][14] by decreasing T cell activation. 11,13,[15][16][17][18] Although more than 50 crystal structures exist for this therapeutic target, [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] only partial structures of the active site, that is, without the refinement of the dynamic JK-loop, were obtained so far. The JK-loop (residues 360-380) of hIDO1 is a dynamic loop located at the entrance of the active site, in contact with the heme cofactor.…”

Section: Introductionmentioning

confidence: 99%

Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo Site

Mirgaux

Leherte

2021

Int J�Tryptophan�Res

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Protein dynamics governs most of the fundamental processes in the human body. Particularly, the dynamics of loops located near an active site can be involved in the positioning of the substrate and the reaction mechanism. The understanding of the functioning of dynamic loops is therefore a challenge, and often requires the use of a multi-disciplinary approach mixing, for example, crystallographic experiments and molecular dynamics simulations. In the present work, the dynamic behavior of the JK-loop of the human indoleamine 2,3-dioxygenase 1 hemoprotein, a target for immunotherapy, is investigated. To overcome the lack of knowledge on this dynamism, the study reported here is based on 3 crystal structures presenting different conformations of the loop, completed with molecular dynamics trajectories and MM-GBSA analyses, in order to trace the reaction pathway of the enzyme. In addition, the crystal structures identify an exo site in the small unit of the enzyme, that is populated redundantly by the substrate or the product of the reaction. The role of this newer reported exo site still needs to be investigated.

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Section: Introductionmentioning

confidence: 99%

Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo Site

Mirgaux

Leherte

2021

Int J�Tryptophan�Res

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“…The most potent analogues were then evaluated for their in vitro metabolic stability. The class, indeed, shares a non‐hindered amide moiety which can be putatively susceptible toward hydrolytic metabolism, as previously observed for other IDO1 inhibitors [54,55] . To rule out this possibility, the candidates ( 2 , 24 , 25 , 38 , 39 , 40 ) were incubated for 1 h in rat liver S9 fraction (RLS9) supplied with NADPH and then the residual substrate was measured.…”

Section: Resultsmentioning

confidence: 97%

The [1,2,4]Triazolo[4,3‐a]pyridine as a New Player in the Field of IDO1 Catalytic Holo‐Inhibitors

et al. 2021

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Inhibitors of indoleamine 2,3‐dioxygenase 1 (IDO1) are considered a promising strategy in cancer immunotherapy as they are able to boost the immune response and to work in synergy with other immunotherapeutic agents. Despite the fact that no IDO1 inhibitor has been approved so far, recent studies have shed light on the additional roles that IDO1 mediates beyond its catalytic activity, conferring new life to the field. Here we present a novel class of compounds originated from a structure‐based virtual screening made on IDO1 active site. The starting hit compound is a novel chemotype based on a [1,2,4]triazolo[4,3‐a]pyridine scaffold, so far underexploited among the heme binding moieties. Thanks to the rational and in silico‐guided design of analogues, an improvement of the potency to sub‐micromolar levels has been achieved, with excellent in vitro metabolic stability and exquisite selectivity with respect to other heme‐containing enzymes.

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“…Insertion of halogen atoms on hit or lead compounds has been used to exploit their steric effects because the formation of halogen groups in ligand–target complexes favorably contributes to the stability of the protein–ligand complex [ 28 , 110 , 111 ]. The use of carbamates in medicinal chemistry has increased, and many derivatives are specifically designed to form drug–target interactions through their carbamate moiety [ 29 , 112 , 113 ]. Fragment-based drug discovery is an effective strategy for generating small-molecule protein inhibitors and drug candidates, which has led to three FDA-approved drugs and clinical trials for nearly 50 molecules [ 114 ].…”

Section: Drug Design Strategies For Covid-19mentioning

confidence: 99%

Computational anti-COVID-19 drug design: progress and challenges

Wang

Zhang

Nie

et al. 2021

Briefings in Bioinformatics

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Vaccines have made gratifying progress in preventing the 2019 coronavirus disease (COVID-19) pandemic. However, the emergence of variants, especially the latest delta variant, has brought considerable challenges to human health. Hence, the development of robust therapeutic approaches, such as anti-COVID-19 drug design, could aid in managing the pandemic more efficiently. Some drug design strategies have been successfully applied during the COVID-19 pandemic to create and validate related lead drugs. The computational drug design methods used for COVID-19 can be roughly divided into (i) structure-based approaches and (ii) artificial intelligence (AI)-based approaches. Structure-based approaches investigate different molecular fragments and functional groups through lead drugs and apply relevant tools to produce antiviral drugs. AI-based approaches usually use end-to-end learning to explore a larger biochemical space to design antiviral drugs. This review provides an overview of the two design strategies of anti-COVID-19 drugs, the advantages and disadvantages of these strategies and discussions of future developments.

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Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors

Cited by 18 publications

References 34 publications

Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo Site

Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo Site

The [1,2,4]Triazolo[4,3‐a]pyridine as a New Player in the Field of IDO1 Catalytic Holo‐Inhibitors

Computational anti-COVID-19 drug design: progress and challenges

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