Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase

Lee, Won Gil; Frey, Kathleen M.; Gallardo‐Macias, Ricardo; Spasov, Krasimir A.; Chan, Albert H.; Anderson, Karen S.; Jorgensen, William L.

doi:10.1016/j.bmcl.2015.06.074

Cited by 17 publications

(22 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). Cmpd I showed significant potency along with remarkable efficacy on clinically relevant drug resistant strains of HIV-1, and lack of cytotoxicity as described previously (Lee, et al, 2016, Lee, et al, 2014, Lee, et al, 2015. In the current study, we further explored Cmpd I as a potential anti-HIV drug candidate by dissecting the molecular mechanism through biochemical and structural studies as well as investigating Cmpd I's in vitro and in vivo pharmacological profiles.…”

Section: Introductionsupporting

confidence: 57%

“…In continuous efforts to develop next-generation NNRTIs with improved antidrug resistance, pharmacokinetics and toxicity profiles we have used computational and structure-based drug design to discover a class of inhibitors known as catechol diethers (Lee, et al, 2016, Lee, et al, 2014, Lee, et al, 2015. One of the most potent inhibitors from this series is Cmpd I (Fig.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV

et al. 2019

Self Cite

View full text Add to dashboard Cite

Combination antiretroviral therapy (cART) has been proven effective in inhibiting human immunodeficiency virus type 1 (HIV-1) infection and has significantly improved the health outcomes in acquired immune deficiency syndrome (AIDS) patients. The therapeutic benefits of cART have been challenged because of the toxicity and emergence of drug-resistant HIV-1 strains along with lifelong patient compliance resulting in non-adherence. These issues also hinder the clinical benefits of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which are one of the vital components of cART for the treatment of HIV-1 infection. In this study, using a computational and structural based drug design approach, we have discovered an effective HIV-1 NNRTI, compound I (Cmpd I) that is very potent in biochemical assays and which targets key residues in the allosteric binding pocket of wild-type (WT)-RT as revealed by structural studies. Furthermore, Cmpd I exhibited very potent antiviral activity in HIV-1 infected T cells, lacked cytotoxicity (therapeutic index >100,000), and no significant off-target effects were noted in pharmacological assays. To address the issue of non-adherence, we developed a long-acting nanoformulation of Cmpd I (Cmpd I-NP) using poly(lactide-coglycolide) (PLGA) particles. The

show abstract

Section: Introductionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…57 Secondly, our cyanovinylphenyl mimics were then merged with the diaminopyrimidine substructure of rilpivirine or the corresponding triazine to give 22 hybrid NNRTIs including 29 and 30 . 58 The activities of these compounds are excellent, and as also intended, there was a dramatic boost in the aqueous solubilities (vide infra). Crystal structures were also reported for desfluoro- 28 , 29 , and 30 bound to WT HIV-RT.…”

Section: Replacement Of the Cyanovinyl Groupmentioning

confidence: 92%

Computer-aided discovery of anti-HIV agents

Jorgensen

2016

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class.

show abstract

“…A structural analysis of key interactions of the most favorable chemical groups has been discussed and corroborates well crystallographic data published by Jorgensen and co-workers. 7,25–30 Furthermore, this study utilized GPU accelerated MD code, enabling the longest protein calculations to finish within 2–3 days, approximately 4–5 times faster than previous central processing unit (CPU)-based simulations. This work initiates future λ dynamics applications by demonstrating the ability to efficiently explore highly dimensional ligand chemical spaces with minimal computational costs compared to FEP/TI methods.…”

mentioning

confidence: 99%

Predicting Binding Free Energies in a Large Combinatorial Chemical Space Using Multisite λ Dynamics

Vilseck

Armacost

Hayes

et al. 2018

J. Phys. Chem. Lett.

View full text Add to dashboard Cite

In this study, we demonstrate the extensive scalability of the biasing potential replica exchange multisite λ dynamics (BP-REX MSλD) free energy method by calculating binding affinities for 512 inhibitors to HIV Reverse Transcriptase (HIV-RT). This is the largest exploration of chemical space using free energy methods known to date, requires only a few simulations, and identifies 55 new inhibitor designs against HIV-RT predicted to be at least as potent as a tight binding reference compound (i.e., as potent as 56 nM). We highlight that BP-REX MSλD requires an order of magnitude less computational resources than conventional free energy methods while maintaining a similar level of precision, overcomes the inherent poor scalability of conventional free energy methods, and enables the exploration of combinatorially large chemical spaces in the context of in silico drug discovery.

show abstract

Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase

Cited by 17 publications

References 14 publications

Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV

Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV

Computer-aided discovery of anti-HIV agents

Predicting Binding Free Energies in a Large Combinatorial Chemical Space Using Multisite λ Dynamics

Contact Info

Product

Resources

About