Browsing by Author "Naik, Siddhi D."

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    Design, Synthesis, and Molecular Docking Analysis of Fluorinated MLN4924 Derivatives as Antiviral Agents
    (John Wiley & Sons, 2023) Sung, Kisu; Hyeon, Seokhwan; Kim, Minjae; Sahu, Pramod K.; Naik, Siddhi D.; Aswar, Vikas R.; Tripathi, Sushil K.; Chang, Tong-Shin; Ahn, Jin-Hyun; Yu, Jinha; Jeong, Lak Shin
    MLN4924 is known for its potential in cancer treatment and antiviral activity as a NEDD8-activating enzyme (NAE) inhibitor. We designed and synthesized fluorinated MLN4924 derivatives by electrophilic fluorination at the 6′-position and nucleophilic fluorination at the 2′-position of the sugar moiety, respectively. The compounds were then evaluated for their anti-HCMV activity, and compound 2 a exhibited the most potent HCMV inhibitory activity, showing similar results to MLN4924 but with no toxicity at a high concentration. Docking studies highlighted the importance of the sugar conformation in the binding interaction with the target protein. This research offers critical insights into the optimization of MLN4924 derivatives and provides a promising pathway towards the development of effective antiviral agents.
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    Exploring C2 and N6 Substituent Effects on Truncated 4′-Thioadenosine Derivatives as Dual A2A and A3 Adenosine Receptor Ligands
    (John Wiley & Sons, 2024) Naik, Siddhi D.; Kim, Minjae; Choi, Jiyoung; Kim, Gibae; Woo Kim, Seung; Aswar, Vikas R.; Tripathi, Sushil K.; Gaikwad, Vidyasagar; Yu, Jinha; Shin Jeong, Lak
    Based on high binding affinity of truncated 2-hexynyl-4′-thioadenosine (3 a) at both A2A adenosine receptor (AR) and A3 AR, we explored structure-activity relationship (SAR) of the C2-substitution by altering chain length of the 2-hexynyl moiety, thereby evaluating the hydrophobic pocket size. A series of truncated N6-substituted 4′-thioadenosine derivatives with C2-alkynyl substitution were successfully synthesized from D-mannose, using a palladium-catalyzed Sonogashira coupling reaction as the key step, whose structures were confirmed by the X-ray crystal structure of 4 h. As the size of the alkynyl group at the C2-position increased, the binding affinity improved; however, when the substituted group was larger than hexynyl, the binding affinity decreased. The introduction of a bulky hydrophobic group such as 3-halobenzyl group at the free N6-amino group decreased the binding affinity at hA2AAR. These results confirm our previous findings that a free amino group at N6-position and longer hydrophobic chain at C2-position are essential for hA2A AR binding affinity. The introduction of a bulky hydrophobic group at free N6-amino group maintained the binding affinity at hA3 AR. The binding mode of truncated 2-substituted-4′-thioadenosine derivatives to hA2A and hA3 AR were predicted by a molecular docking study.
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    Stereochemical influence of 4ʹ-methyl substitutions on truncated 4ʹ-thioadenosine derivatives: Impact on A3 adenosine receptor binding and antagonism
    (Elsevier, 2024) Kim, Minjae; Naik, Siddhi D.; Jarhad, Dnyandev B.; Aswar, Vikas R.; Tripathi, Sushil K.; Aslam, Muhammad Arif; Huh, Joo Young; Jeong, Lak Shin
    Herein, we investigated the stereochemical effects of 4ʹ-methyl substitution on A3 adenosine receptor (A3AR) ligands by synthesizing and evaluating a series of truncated 4ʹ-thioadenosine derivatives featuring 4ʹ-α-methyl, 4ʹ-β-methyl, and 4ʹ,4ʹ-dimethyl substitutions. We successfully synthesized these derivatives, using the stereoselective addition of an organometallic reagent, KSAc-mediated sulfur cyclization, and Vorbrüggen condensation. Binding assays demonstrated that the 4ʹ-β-methyl substitution conferred the highest affinity for A3AR, with compound 1 h exhibiting a Ki = 3.5 nM, followed by the 4ʹ,4ʹ-dimethyl and 4ʹ-α-methyl substitutions. Notably, despite the absence of the 5ʹ-OH group, compound 1 h unexpectedly displayed partial agonism. Computational docking studies indicated that compound 1 h, the β-methyl derivative, adopted a South conformation and maintained strong interactions within the receptor, including a critical interaction with Thr94, a residue known to be notable for agonistic effects. Conversely, compound 2 h, the α-methyl derivative, also adopted a South conformation but resulted in a flattened structure that hindered interactions with Thr94 and Asn250. The dimethyl derivative 3 h exhibited steric clashes with Thr94, contributing to a reduction in binding affinity. However, the docking results for 3 h indicated a North conformation, suggesting that the change in sugar conformation due to the additional 4ʹ-methyl group altered the angle between the α-methyl group and the sugar plane, enabling binding despite the increased steric bulk. These findings suggest that not only do the substituents and their stereochemistry influence receptor–ligand interactions, but the conformation and the resulting spatial orientation of the substituents also play a crucial role in modulating receptor–ligand interaction. This stereochemical insight offers a valuable framework for the design of new, selective, and potent A3AR ligands, potentially facilitating the development of novel therapeutics for A3AR-related diseases such as glaucoma, inflammation, and cancer.