Identification of Tripeptide Inhibitors Targeting MAPK3 in Leishmania martiniquensis and Leishmania orientalis Using Molecular Modeling, Virtual Screening, Molecular Dynamics, and In Vitro Approach

Article

作者: Kumsiri, Nutnaree ; Kiriwan, Duangnapa ; Vieira, Tatiana F. ; Sousa, Sergio F. ; Choowongkomon, Kiattawee

MAPK3 has been identified as a potential drug target due to its role in the Leishmania life cycle. This study focused on two species prevalent in Thailand: Leishmania martiniquensis and Leishmania orientalis. Using an in silico strategies, we screened an in-house library of 8000 tripeptides to identify potential MAPK3 inhibitors. A multi-level computational workflow was employed, including homology modeling, molecular docking study, and molecular dynamics (MD) simulations. Promising candidates were further validated by an in vitro kinase assay. The three-dimensional (3D) structures of MAPK3 from L.martiniquensis and L. orientalis were constructed by using the Swiss Model. Structure-based virtual screening identified nine promising tripeptides, with WSY demonstrated strong binding affinity, MD simulation and MM-GBSA binding free energy calculation confirmed its stable interaction with key regions in the MAPK3 active site, including the DFG motif, hinge region, αC-helix through hydrogen bonds, hydrophobic interaction, and π-π stacking. In vitro kinase assays demonstrated that the peptide WSY was significantly more effective at inhibiting MAPK3 than WHW, with IC₅₀ values of 0.9 ± 11.3 and 26.9 ± 6.7 μM, respectively. These findings suggest that WSY is a promising anti-leishmanial drug candidate targeting LmqMAPK3 and LoMAPK3. Our hybrid computational-experimental approach provides a solid framework for identification of novel inhibitors and can be extended to other compound libraries to help the discovery of new anti-leishmania therapies.

1997-05-01·Journal of medicinal chemistry1区 · 医学

Potent Noncovalent Thrombin Inhibitors That Utilize the Unique Amino Acid d-Dicyclohexylalanine in the P3 Position. Implications on Oral Bioavailability and Antithrombotic Efficacy

1区 · 医学

Article

作者: Vacca, Joseph P. ; Lyle, Elizabeth A. ; Dancheck, Kimberley B. ; Baskin, Elizabeth P. ; Lumma, William C. ; Tucker, Thomas J. ; Lynch, Joseph J. ; Lewis, S. Dale ; Appleby, Sandra D. ; Gardell, Stephen J. ; Lucas, Bobby J. ; Woltmann, Richard ; Chen, I-Wu

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.

100 项与 Tripeptide Inhibitors (Kasetsart University) 相关的药物交易

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