Tweaking α-Galactoceramides: Probing the Dynamical Mechanisms of Improved Recognition for Invariant Natural Killer T-cell Receptor in Cancer Immunotherapeutics

Abstract

Background: The last few decades have witnessed ground breaking research geared towards immune surveillance mechanisms and have yielded significant improvements in the field of cancer immunotherapy. This approach narrows down on the development of therapeutic agents that either activate or enhance the recognitive function of the immune system to facilitate the destruction of malignant cells. The α-galactosylceramide derivative; KRN7000, is an immunotherapeutic agent that has gained attention due to its pharmacological ability to activate CD1d-restricted invariant natural killer T (iNKT) cells with notable potency against cancer cells in mouse models, a therapeutic success was not well replicated in human models. Dual structural modification of KRN700 entailing the incorporation of hydrocinnamoyl ester on C6’’ and C4-OH truncation of the sphingoid base led to the development of AH10-7 which, interestingly, exhibited high potency in human cells. Objective/Methods: Therefore, to gain atomistic insights into the structural dynamics and selective mechanisms of AH107 for human variants, we employed integrative molecular dynamics simulations and thermodynamic calculations to investigate the differential inhibitory activities of KRN7000 and AH10-7 on hTCR-CD1d towards activating iNKT. Results: Interestingly, our findings revealed that AH10-7 exhibited higher affinity binding and structural effects on hTCR-CD1d, as mediated by the incorporated hydrocinnamoyl ester moiety which accounted for stronger intermolecular interactions with ‘non-common’ binding site residues. Conclusions: Findings extracted from this study further reveal important atomistic perspectives that could aid in the design of novel α-GalCer derivatives for cancer immunotherapeutics.

Dual‐Inhibition of Human N‐Myristoyltransferase Subtypes Halts Common Cold Pathogenesis: Atomistic Perspectives from the Case of IMP‐1088**

“…After the observed similarity in interacting residues in both HsNMT1 and HsNMT2 upon binding of IMP‐1088, we quantified the individual residues′ specific energy contributions towards the overall binding within the pockets. This was performed by calculation of per‐residue based energy decomposition using the MM/PBSA incorporated approach [48–50] . As shown in Figure 6, prominent energy contributions of active site residues were observed, with most having total energy contributions <−1, confirming their cruciality to the overall total binding of compound IMP‐1088 [51] .…”

Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor

“…Thus, we investigated further a-galactosyl-lipids (11)(12)(13)(14)(15)(16)(17)(19)(20)(21)(22) derived from KRN7000 (18) mainly with modification of the fatty acid residue. KRN7000 (18) had previously been found to display immunostimulatory and antitumor activity in several in vivo models, and was advanced to clinical trials [29][30][31] .…”