Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

Yue, Yang; Zhang, Sirui; Zhou, Qian; Zhang, Chen; Gao, Yuqi; Wang, Hao; Li, Zhe; Wu, Deyan; Wu, Yinuo; Huang, Yi‐You; Guo, Lei; Luo, Hai‐Bin

doi:10.1016/j.apsb.2020.04.003

Cited by 19 publications

(19 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Paraffin-embedded tissues were sliced at a thickness of 5 μm and mounted on glass slides. Tissue sections were stained with hematoxylin and eosin (HE) as previously described . Pulmonary vascular remodeling was assessed by measuring the percent medial wall thickness of vessels (50–200 μm diameter).…”

Section: Methodsmentioning

confidence: 99%

“…Tissue sections were stained with hematoxylin and eosin (HE) as previously described. 33 Pulmonary vascular remodeling was assessed by measuring the percent medial wall thickness of vessels (50−200 μm diameter). Vessel's external diameter and medial wall thickness (MT) were measured using a light microscope by an observer who was blinded to the treatment of rats.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket

et al. 2020

Self Cite

View full text Add to dashboard Cite

Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the Hloop with a maximum 24 Å movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the meantime, the interfacing surface area between monomers also decreased ( Table S3 ), further weakening the intramolecular interactions and destabilizing dimerization. Moreover, by calculating the binding free energy between the ROC monomers with Molecular Mechanics/Poison Boltzmann Surface Area [ 49 , 50 , 51 ] (MM/PBSA), we further confirmed that ROCs, when bounded by GTP, were indeed less dimerized and therefore more prone to form the catalytically active monomers with hydrolysis activity than to be bound by its GDP counterparts.…”

Section: Resultsmentioning

confidence: 52%

Markov State Models and Molecular Dynamics Simulations Provide Understanding of the Nucleotide-Dependent Dimerization-Based Activation of LRRK2 ROC Domain

et al. 2021

Molecules

View full text Add to dashboard Cite

Mutations in leucine-rich repeat kinase 2 (LRRK2) are recognized as the most frequent cause of Parkinson’s disease (PD). As a multidomain ROCO protein, LRRK2 is characterized by the presence of both a Ras-of-complex (ROC) GTPase domain and a kinase domain connected through the C-terminal of an ROC domain (COR). The bienzymatic ROC–COR–kinase catalytic triad indicated the potential role of GTPase domain in regulating kinase activity. However, as a functional GTPase, the detailed intrinsic regulation of the ROC activation cycle remains poorly understood. Here, combining extensive molecular dynamics simulations and Markov state models, we disclosed the dynamic structural rearrangement of ROC’s homodimer during nucleotide turnover. Our study revealed the coupling between dimerization extent and nucleotide-binding state, indicating a nucleotide-dependent dimerization-based activation scheme adopted by ROC GTPase. Furthermore, inspired by the well-known R1441C/G/H PD-relevant mutations within the ROC domain, we illuminated the potential allosteric molecular mechanism for its pathogenetic effects through enabling faster interconversion between inactive and active states, thus trapping ROC in a prolonged activated state, while the implicated allostery could provide further guidance for identification of regulatory allosteric pockets on the ROC complex. Our investigations illuminated the thermodynamics and kinetics of ROC homodimer during nucleotide-dependent activation for the first time and provided guidance for further exploiting ROC as therapeutic targets for controlling LRRK2 functionality in PD treatment.

show abstract

“…The Δ G nonpolar was calculated using the function of the solvent accessible surface area (SASA) with the γ value of 0.0072 kcal/(mol Å 2 ) and the b value of 0 kcal/mol. The T Δ S was not computed in this work because of the extremely long durations of normal mode analysis for large systems ( Wang et al, 2019 ; Yang et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Liang

Wang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

show abstract

Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

Cited by 19 publications

References 30 publications

Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket

Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket

Markov State Models and Molecular Dynamics Simulations Provide Understanding of the Nucleotide-Dependent Dimerization-Based Activation of LRRK2 ROC Domain

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Contact Info

Product

Resources

About