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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
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Jitonnom, Wijitra
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Tue-Ngeun, Panthip
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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; q2= 0.506, r2= 0.875, SEE = 0.227 and CoMSIA; q2= 0.614, r2= 0.871, SEE = 0.230). Key structural features are drawn from the models: The R1substituent prefers small, less steric groups, while the R2substituent favors larger, more sterically bulky hydrophobic groups. Introducing hydrogen bond acceptor and donor groups at R2and 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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3D-QSAR and molecular docking studies of peptide-hybrids as dengue virus NS2B/NS3 protease inhibitors
(2024-06-01)
Jitonnom, Jitrayut
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Meelua, Wijitra
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Tue-nguen, Panthip
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Saparpakorn, Patchreenart
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Hannongbua, Supa
Global warming and climate change have made dengue disease a global health issue. More than 50 % of the world's population is at danger of dengue virus (DENV) infection, according to the World Health Organization (WHO). Therefore, a clinically approved dengue fever vaccination and effective treatment are needed. Peptide medication development is new pharmaceutical research. Here we intend to recognize the structural features inhibiting the DENV NS2B/NS3 serine protease for a series of peptide-hybrid inhibitors (R<inf>1</inf>–R<inf>2</inf>-Lys-R<inf>3</inf>-NH<inf>2</inf>) by the 3D-QSAR technique. Comparative molecular field analysis (q2 = 0.613, r2 = 0.938, r2<inf>pred</inf> = 0.820) and comparative molecular similarity indices analysis (q2 = 0.640, r2 = 0.928, r2<inf>pred</inf> = 0.693) were established, revealing minor, electropositive, H-bond acceptor groups at the R<inf>1</inf> position, minor, electropositive, H-bond donor groups at the R<inf>2</inf> position, and bulky, hydrophobic groups at the R<inf>3</inf> position for higher inhibitory activity. Docking studies revealed extensive H-bond and hydrophobic interactions in the binding of tripeptide analogues to the NS2B/NS3 protease. This study provides an insight into the key structural features for the design of peptide-based inhibitors of DENV NS2B/NS3 protease.
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New potent epitopes from Leptospira borgpetersenii for the stimulation of humoral and cell-mediated immune responses: Experimental and theoretical studies
(2021-01-01)
Tansiri, Yada
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Sritrakul, Tepyuda
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Saparpakorn, Patchreenart
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Boondamnern, Timporn
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Chimprasit, Aunlika
The rhKU_Sej_LRR_2271 protein is introduced as one of the leptospiral vaccine candidates since it contains the predicted immunogenic epitopes. The in-silico sequence and structural based analysis have been used in this study to analyze MHC class I and class II-restricted epitopes of the protein. Six epitope prediction programs were employed, which the epitopes with high prediction scores from each program were aligned. The 21 of potentially unrestrained epitopes with prediction scores above the cut-off value from at least two prediction programs were selected. The 3D-molecular modeling, docking, and molecular dynamic simulation were performed to evaluate the affinity binding between peptide-MHC complex and T-cell receptor. One promising epitope, which is 171-LLFLPLIKI, showed the potency in binding to both MHC class I and II alleles. Two newly designed peptides containing epitopes which can bind to over 3 of MHC alleles, LL17:171-LLFLPLIKILYVDRNKL-187 and SL19:209-SLNSGIKALPFNYEKLVNL-227, significantly increased interferon-gamma (IFNg)-producing specific T-cell responses in the rhKU_Sej_LRR_2271 immunized rabbits compared to nonimmunized rabbits. The LL17 peptide can also induce interferon-gamma-producing specific CD4+ T-cell responses in the immunized rabbits. For the evaluation of humoral immune responses, the immunized rabbits have a significantly greater amount of specific IgG in plasma than the nonimmunized rabbits. Ex-vivo study of T-cell responses in animal model using flow cytometry confirmed an accomplishment of the theoretically in-silico analysis for discovering potential T-cell epitopes of the protein. The results show that the rhKU_Sej_LRR_2271 protein containing promiscuous T-cell epitopes, which can induce both humoral and cell-mediated immune responses, is a prospective protein candidate for leptospiral vaccine development.
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Diptoindonesin D, a potent antibacterial activity against gram-positive bacteria, an inhibitor of penicillin-binding protein 2a from the stem bark of Shorea roxburghii G.Don
(2019-11-01)
Sudto, Kanokorn
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Saparpakorn, Patchreenart
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Tancharoen, Chompoonuch
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Phromyothin, Darinee
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Techasakul, Supanna
The emergence and spread of antimicrobial resistance (AMR) is a serious threat to public human health. The challenge now is an urgent need to new potent antibiotics combating AMR which can be an effective way to solve the crisis. A new potent antibacterial activity of diptoindonesin D, together with four known compounds as hopeafuran, α-viniferan, hopeahainol A and hopeahainol C were isolated from the stem bark of Shorea roxburghii G. Don in Khon Kaen province, Thailand. Diptoindonesin D were screened for antimicrobial activity and possesses significant activity minimum inhibitory concentrations (MIC) values of 4.68 and 9.37 μg/mL against Staphylococcus epidermidis and Staphylococcus aureus, respectively. The absolute configuration of diptoindonesin D were evaluated by circular dichroism (ECD) calculations. The ECD results indicated that the possible configuration of diptoindonesin D should be R-configuration. Furthermore, reverse docking was performed to identify the protein target of diptoindonesin D based on four scoring functions using GOLD program. This investigation is the first time that reveals interaction between diptoindonesin D and its binding with cell wall synthesis protein targets. The results highlighted that, penicillin-binding protein 2a (PBP2a), an antibacterial cell wall, might be the potential target for the binding of diptoindonesin D. The obtained results can be useful as a guideline for the development of effective diptoindonesin D as a PBP2a inhibitor.

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