The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic

Namasivayam, Vigneshwaran; Vanangamudi, Murugesan; Kramer, Victor G.; Kurup, Sonali; Zhan, Peng; Liu, Xinyong; Kongsted, Jacob; Byrareddy, Siddappa N.

doi:10.1021/acs.jmedchem.8b00843

Cited by 142 publications

(95 citation statements)

References 205 publications

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“…It binds to an allosteric hydrophobic pocket, also named the NNRTI-binding pocket (NNIBP), located 10 Å from the DNA catalytic active site of reverse transcriptase (RT). With the efforts of the past decades, six NNRTIs were approved by the FDA (Figure 1) [8]. Nevirapine (NVP), delavirdine (DLV), and efavirenz (EFV), the first-generation NNRTIs, bind to NNIBP in a rigid "butterfly-like" binding mode, commonly less active toward the mutant strains [9].…”

Section: Introductionmentioning

confidence: 99%

Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

et al. 2020

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The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure–activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.

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Section: Introductionmentioning

confidence: 99%

Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

et al. 2020

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“…The protocol is a computational representation of a putative ligand that binds to the intended binding site and is a unique and essential element of the docking algorithm. The scoring function in Surflex-Dock, which contains hydrophobic, polar, repulsive, entropic, and solvation terms, was trained to estimate the dissociation constant (K d ) expressed in −log (K d ) 2 . The scoring function in Surflex-Dock, which contains hydrophobic, polar, repulsive, entropic, and solvation terms, was trained to estimate the binding energy.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…The structure optimization was performed for more than 10,000 generations using a genetic algorithm, and the 20 best-scoring ligand-protein complexes were kept for further analyses. The −log(K d ) 2 values of the 20 best-scoring complexes, which represented the binding affinities of the ligand with RT, encompassed a wide scope of the functional classes (10 −2 -10 −9 ). Only the highest scoring 3D structural model of the ligand-bound RT was chosen to define the binding interaction.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…Over the past decades, more than fifty structurally diverse classes of compounds have been reported as NNRTIs, which can be divided into the following categories according to their structures: TIBO (tetrahydroimidazobenzodiazepinone), α-APA (α-anilinophenylacetamide), ITU (iminothiourea), DABO (dihydro-alkoxy-benzyl-oxopyrimidine), DATA (diaryltriazine), DAPY (diarylpyrimidine), etc. [2,3]. Diarylpyrimidine (DAPY) derivatives are second-generation NNRTIs with remarkable anti-HIV-1 activity and favorable pharmacological properties [4].…”

Section: Introductionmentioning

confidence: 99%

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Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs

Pannecouque

Clercq

et al. 2020

Molecules

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Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds B4 (EC50 = 6 nM) and B6 (EC50 = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC50 values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC50 = 0.08 μM). The preliminary structure–activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.

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“…Six HIV-1 NNRTIs including nevirapine, delavirdine, efavirenz, etravirine (ETV), rilpivirine (RPV), and doravirine have been approved by US Food and Drug Administration for clinical use to date (Namasivayam et al, 2019). ETV and RPV (Figure 1), which belong to diarylpyrimidine (DAPY) derivatives that were recognized as one of the most effective families of NNRTIs, have attracted considerable attention due to their excellent potency against HIV-1 wild-type and mutant strains.…”

Section: Introductionmentioning

confidence: 99%

In silico Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines

et al. 2020

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A novel series of dihydrofuro[3,4-d]pyrimidine (DHPY) analogs have recently been recognized as promising HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with potent antiviral activity. To better understand the pharmacological essentiality of these DHPYs and design novel NNRTI leads, in this work, a systematic in silico study was performed on 52 DHPYs using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, virtual screening, absorption-distribution-metabolism-excretion (ADME) prediction, and molecular dynamics (MD) methods. The generated 3D-QSAR models exhibited satisfactory parameters of internal validation and well-externally predictive capacity, for instance, the q 2 , R 2 , and r pred 2 of the optimal comparative molecular similarity indices analysis model were 0.647, 0.970, and 0.751, respectively. The docking results indicated that residues Lys101, Tyr181, Tyr188, Trp229, and Phe227 played important roles for the DHPY binding. Nine lead compounds were obtained by the virtual screening based on the docking and pharmacophore model, and three new compounds with higher docking scores and better ADME properties were subsequently designed based on the screening and 3D-QSAR results. The MD simulation studies further demonstrated that the newly designed compounds could stably bind with the HIV-1 RT. These hit compounds were supposed to be novel potential anti-HIV-1 inhibitors, and these findings could provide significant information for designing and developing novel HIV-1 NNRTIs.

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The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic

Cited by 142 publications

References 205 publications

Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy

Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs

In silico Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines

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