Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design

Oum, Yoon Hyeun; Kell, Steven A.; Yoon, Younghyoun; Liang, Zhongxing; Burger, Pieter B.; Shim, Hyunsuk

doi:10.1016/j.ejmech.2020.112479

Cited by 10 publications

(8 citation statements)

References 56 publications

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“…LB techniques are generally used in the prefiltering step, as illustrated in different works that have exploited 2D fingerprints [ 81 , 82 ], 3D molecular similarity [ 83 , 84 , 85 ] and pharmacophore models [ 86 , 87 , 88 ]. To enhance the drug-likeness of the compounds, knowledge-based in silico ADMET or pan-assay interference compounds (PAINS; [ 89 ]) filters can also be applied.…”

Section: Sequential Lb and Sb Methodsmentioning

confidence: 99%

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Vázquez

Lopez

Gibert³

et al. 2020

Molecules

124

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Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued efforts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature.

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Section: Sequential Lb and Sb Methodsmentioning

confidence: 99%

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Vázquez

Lopez

Gibert³

et al. 2020

Molecules

124

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show abstract

“…Computational modeling has been carried out to determine the interaction sites of different CXCR4 receptor ligands with the binding pockets of CXCR4 21 , 22 . Several molecular dynamics (MD) studies are reported, primarily (i) to characterize the structure and function of CXCR4 and agonist binding 23 – 25 , (ii) to study the interactions between CXCR4 and small molecule/peptide antagonists 26 – 28 , and (iii) to address the dimerization of CXCR4 29 – 31 . However, the interactions of EPI-X4 with CXCR4 have so far not been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

Computational modeling and experimental validation of the EPI-X4/CXCR4 complex allows rational design of small peptide antagonists

et al. 2021

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EPI-X4, a 16-mer fragment of albumin, is a specific endogenous antagonist and inverse agonist of the CXC-motif-chemokine receptor 4 (CXCR4) and thus a key regulator of CXCR4 function. Accordingly, activity-optimized synthetic derivatives of EPI-X4 are promising leads for the therapy of CXCR4-linked disorders such as cancer or inflammatory diseases. We investigated the binding of EPI-X4 to CXCR4, which so far remained unclear, by means of biomolecular simulations combined with experimental mutagenesis and activity studies. We found that EPI-X4 interacts through its N-terminal residues with CXCR4 and identified its key interaction motifs, explaining receptor antagonization. Using this model, we developed shortened EPI-X4 derivatives (7-mers) with optimized receptor antagonizing properties as new leads for the development of CXCR4 inhibitors. Our work reveals the molecular details and mechanism by which the first endogenous peptide antagonist of CXCR4 interacts with its receptor and provides a foundation for the rational design of improved EPI-X4 derivatives.

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“…Virtual screening allows a search for several chemical libraries of small molecules and selects those that best interact with the specific target’s catalytic site [ 94 , 143 , 144 , 145 ]. The application of this technique is well accepted, mainly in the lead discovery phase [ 146 , 147 ].…”

Section: Search For New Therapeutic Options—a Journeymentioning

confidence: 99%

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

Kioshima

Mendonca

Teixeira

et al. 2021

JoF

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Paracoccidioidomycosis (PCM) is a notable fungal infection restricted to Latin America. Since the first description of the disease by Lutz up to the present day, Brazilian researchers have contributed to the understanding of the life cycle of this pathogen and provided the possibility of new targets for antifungal therapy based on the structural and functional genomics of Paracoccidioides. In this context, in silico approaches have selected molecules that act on specific targets, such as the thioredoxin system, with promising antifungal activity against Paracoccidioides. Some of these are already in advanced development stages. In addition, the application of nanostructured systems has addressed issues related to the high toxicity of conventional PCM therapy. Thus, the contribution of molecular biology and biotechnology to the advances achieved is unquestionable. However, it is still necessary to transcend the boundaries of synthetic chemistry, pharmaco-technics, and pharmacodynamics, aiming to turn promising molecules into newly available drugs for the treatment of fungal diseases.

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Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design

Cited by 10 publications

References 56 publications

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Computational modeling and experimental validation of the EPI-X4/CXCR4 complex allows rational design of small peptide antagonists

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

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