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    3D-QSAR studies of 4-aminoquinoline-pyrimidine hybrids as antimalarial inhibitors targeting wild-type P. falciparum dihydrofolate reductase
    (2025-11-01)
    Jitonnom, Jitrayut
    ;
    Jitonnom, Wijitra
    ;
    Tue-Ngeun, Panthip
    ;
    Saparpakorn, Patchreenart
    ;
    Hannongbua, Supa
    Three-dimensional quantitative structure–activity relationship (3D-QSAR) was determined on a set of 4-aminoquinoline-pyrimidine hybrids to elucidate the 3D structural features affecting the antimalaria activity against wild-type Plasmodium falciparum dihydrofolate reductase (PfDHFR). Several combined analyses of comparative molecular field (CoMFA), comparative molecular similarity indices (CoMSIA) and noncovalent interaction (NCI) were carried out. The 3D descriptors capturing steric, electrostatic and hydrophobic features of molecules and their correlation with experimental activity were established (CoMFA; q<sup>2</sup>= 0.506, r<sup>2</sup>= 0.875, SEE = 0.227 and CoMSIA; q<sup>2</sup>= 0.614, r<sup>2</sup>= 0.871, SEE = 0.230). Key structural features are drawn from the models: The R<sup>1</sup>substituent prefers small, less steric groups, while the R<sup>2</sup>substituent favors larger, more sterically bulky hydrophobic groups. Introducing hydrogen bond acceptor and donor groups at R<sup>2</sup>and the N-substituted linkage enhances activity. The docking and NCI results revealed extensive hydrophobic interactions and its stabilization to the binding process of PfDHFR.
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    Development of a Broad-Spectrum Pan-Mpox Vaccine via Immunoinformatic Approaches
    (2025-08-01)
    Puagsopa, Japigorn
    ;
    Jumpalee, Panuwid
    ;
    Dechanun, Sittichoke
    ;
    Choengchalad, Sukanya
    ;
    Lohasupthawee, Pana
    Monkeypox virus (MPXV) has caused 148,892 confirmed cases and 341 deaths from 137 countries worldwide, as reported by the World Health Organization (WHO), highlighting the urgent need for effective vaccines to prevent the spread of MPXV. Traditional vaccine development is low-throughput, expensive, time consuming, and susceptible to reversion to virulence. Alternatively, a reverse vaccinology approach offers a rapid, efficient, and safer alternative for MPXV vaccine design. Here, MPXV proteins associated with viral infection were analyzed for immunogenic epitopes to design multi-epitope vaccines based on B-cell, CD4+, and CD8+ epitopes. Epitopes were selected based on allergenicity, antigenicity, and toxicity parameters. The prioritized epitopes were then combined via peptide linkers and N-terminally fused to various protein adjuvants, including PADRE, beta-defensin 3, 50S ribosomal protein L7/12, RS-09, and the cholera toxin B subunit (CTB). All vaccine constructs were computationally validated for physicochemical properties, antigenicity, allergenicity, safety, solubility, and structural stability. The three-dimensional structure of the selected construct was also predicted. Moreover, molecular docking and molecular dynamics (MD) simulations between the vaccine and the TLR-4 immune receptor demonstrated a strong and stable interaction. The vaccine construct was codon-optimized for high expression in the E. coli and was finally cloned in silico into the pET21a (+) vector. Collectively, these results could represent innovative tools for vaccine formulation against MPXV and be transformative for other infectious diseases.
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    Cry4Aa and Cry4Ba Mosquito-Active Toxins Utilize Different Domains in Binding to a Particular Culex ALP Isoform: A Functional Toxin Receptor Implicating Differential Actions on Target Larvae
    (2022-10-01)
    Dechkla, Manussawee
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    Charoenjotivadhanakul, Sathapat
    ;
    Imtong, Chompounoot
    ;
    Visitsattapongse, Sarinporn
    ;
    Li, Hui Chun
    The three-domain Cry4Aa toxin produced from Bacillus thuringiensis subsp. israelensis was previously shown to be much more toxic to Culex mosquito larvae than its closely related toxin—Cry4Ba. The interaction of these two individual toxins with target receptors on susceptible larval midgut cells is likely to be the critical determinant in their differential toxicity. Here, two full-length membrane-bound alkaline phosphatase (mALP) isoforms from Culex quinquefasciatus larvae, Cq-mALP1263and Cq-mALP1264, predicted to be GPI-linked was cloned and functionally expressed in Spodoptera frugiperda (Sf9) cells as 57- and 61-kDa membrane-bound proteins, respectively. Bioinformatics analysis disclosed that both Cq-mALP isoforms share significant sequence similarity to Aedes aegypti-mALP—a Cry4Ba toxin receptor. In cytotoxicity assays, Sf9 cells expressing Cq-mALP1264, but not Cq-mALP1263, showed remarkably greater susceptibility to Cry4Aa than Cry4Ba, while immunolocalization studies revealed that both toxins were capable of binding to each Cq-mALP expressed on the cell membrane surface. Molecular docking of the Cq-mALP1264-modeled structure with individual Cry4 toxins revealed that Cry4Aa could bind to Cq-mALP1264 primarily through particular residues on three surface-exposed loops in the receptor-binding domain—DII, including Thr<sup>512</sup>, Tyr<sup>513</sup> and Lys<sup>514</sup> in the β10-β11loop. Dissimilarly, Cry4Ba appeared to utilize only certain residues in its C-terminal domain—DIII to interact with such a Culex counterpart receptor. Ala-substitutions of selected β10-β11loop residues (T512A, Y513A and K514A) revealed that only the K514A mutant displayed a drastic decrease in biotoxicity against C. quinquefasciatus larvae. Further substitution of Lys<sup>514</sup> with Asp (K514D) revealed a further decrease in larval toxicity. Furthermore, in silico calculation of the binding affinity change (ΔΔG<inf>bind</inf>) in Cry4Aa-Cq-mALP1264 interactions upon these single-substitutions revealed that the K514D mutation displayed the largest ΔΔG<inf>bind</inf> value as compared to three other mutations, signifying an adverse impact of a negative charge at this critical receptor-binding position. Altogether, our present study has disclosed that these two related-Cry4 mosquito-active toxins conceivably exploited different domains in functional binding to the same Culex membrane-bound ALP isoform—Cq-mALP1264 for mediating differential toxicity against Culex target larvae.