Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120

Curreli, Francesca; Kwon, Young Do; Belov, Dmitry S.; Ramesh, Ranjith; Kurkin, Alexander V.; Altieri, Andrea; Kwong, Peter D.; Debnath, Asim K.

doi:10.1021/acs.jmedchem.7b00179

Cited by 62 publications

(108 citation statements)

References 73 publications

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“…We evaluated those compounds against a selection of 34 HIV-1 clones of clinical isolates of subtypes A, B, C, and D and of recombinant subtype A (A rec ), including A1/D, A2/D, and AG. We compared the three selected compounds with the previously described compound NBD-14113 [13] . We found that the three polycyclic compounds exhibited anti-HIV-1 activity at low micromolar concentrations, with overall mean IC 50 values very similar to that of NBD-14113 (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…We used NBD-556 (an HIV-1 entry agonist [13, 15] ) as a control. Although NBD-556 enhanced the infection of the Cf2Th-CCR5 cells, we found that none of the new polycyclic NBD compounds enhanced HIV-1 infectivity in those cells.…”

Section: Resultsmentioning

confidence: 99%

“…The chemical structure of NBD-556, YYA-021 [6] , and our next-generation lead compounds [1a, 4, 7] .…”

Section: Figurementioning

confidence: 99%

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Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120

et al. 2018

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The pathway by which HIV-1 enters host cells is a prime target for novel drug discovery because of its critical role in the HIV-1 life cycle. The HIV-1 envelop glycoprotein gp120 plays an important role in initiating virus entry by targeting the primary cell receptor CD4. We explored the substitution of bulky molecular groups in region I in the NBD class of entry inhibitors. Previous attempts at bulky substitutions in that region abolished the antiviral activity, even though the binding site is hydrophobic. We synthesized a series of entry inhibitors containing 1,3-benzodioxolyl moiety or its bioisostere, 2,1,3-benzothiadiazole. The introduction of the bulkier groups was well tolerated, and despite only minor improvements in antiviral activity, the selectivity index (SI) improved significantly.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120

et al. 2018

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“…The available crystal structure of a gp120 protein with ligand 82M will be taken from protein data bank (PDB id 5U6E) 15 . The parameters and missing hydrogen for gp120 were prepared using LEAP module of AMBER package 16 using amber ff12SB force filed.…”

Section: Methodsmentioning

confidence: 99%

“…As suggested from the x-ray structure of NBD-11021, it bounds to HIV-1 env gp120 and gives rise to a conclusion that this molecule binds to the Phe43 cavity 14 . The energetic contribution of each amino acid was verified at the binding site involved in stabilizing the complex, ( PDB: 5U6E) 15 …”

Section: Introductionmentioning

confidence: 99%

"Unraveling Key Interactions That Leads the Stability of NBD-14010 Binding to Gp120 of Hiv-1: An Md Simulations and Free Energy Perspectives"

2018

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The contact between gp120 and CD4 binding site leads the HIV-1 entry into the host membrane and therefore, gp120 and CD4 binding sites become a fertile target for many drug discovery projects. The drug NBD-14010, like its predecessor NBD-11021 is a small molecule that can stuff the interactions between gp120 and CD4, and has shown good clinical potency. MD simulation and free energy calculations are used in the present study to focus the thermodynamical insight of binding of NBD-14010 in CD4 binding sites. The energetic of binding of NBD-14010 clearly shows a hydrophobic interaction driven binding of the drug which specifically targets CD4 binding loops. The residue wise free energy decomposition reveals Asn 286 and Trp 288 as key residues stabilizing the binding of NBD-14010 while indicating few more important amino acids in the vicinity of the Phe43 cavity which may also be targeted for further inhibition of HIV-1 entry.

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HIV‐1 Entry Inhibitors: A Review of Experimental and Computational Studies

Rad

Saghaie

Fassihi

2018

Chemistry & Biodiversity

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The HIV-1 life cycle consists of different events, such as cell entry and fusion, virus replication, assembly and release of the newly formed virions. The more logical way to inhibit HIV transmission among individuals is to inhibit its entry into the immune host cells rather than targeting the intracellular viral enzymes. Both viral and host cell surface receptors and co-receptors are regarded as potential targets in anti-HIV-1 drug design process. Because of the importance of this topic it was decided to summarize recent reports on small-molecule HIV-1 entry inhibitors that have not been considered in the latest released reviews. All the computational studies reported in the literature regarding HIV-1 entry inhibitors since 2014 was also considered in this review.

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Synthesis, Antiviral Potency, in Vitro ADMET, and X-ray Structure of Potent CD4 Mimics as Entry Inhibitors That Target the Phe43 Cavity of HIV-1 gp120

Cited by 62 publications

References 73 publications

Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120

Synthesis, Antiviral Activity, and Structure–Activity Relationship of 1,3‐Benzodioxolyl Pyrrole‐Based Entry Inhibitors Targeting the Phe43 Cavity in HIV‐1 gp120

"Unraveling Key Interactions That Leads the Stability of NBD-14010 Binding to Gp120 of Hiv-1: An Md Simulations and Free Energy Perspectives"

HIV‐1 Entry Inhibitors: A Review of Experimental and Computational Studies

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