CF₃‐Pyridinyl Substitution on Antimalarial Therapeutics: Probing Differential Ligand Binding and Dynamical Inhibitory Effects of a Novel Triazolopyrimidine‐Based Inhibitor on Plasmodium falciparum Dihydroorotate Dehydrogenase

Abstract

The quest for reliable dihydroorotate dehydrogenase (DHODH) inhibitors has engendered the discovery of potential therapeutic compounds at different stages of clinical trials. Although promising, high attrition rates and unfavorable bioactivities have limited their drug developmental progress. A recent structural modification of DSM265, a triazolopyrimidine-based inhibitor, yielded DSM421, derived by the substitution of the SF 5 -aniline group on DSM265 with a CF 3 -pyridinyl moiety. Consequently, DSM421 exhibited improved pharmacological and pharmacokinetics attributes relative to DSM265. The improved bioactivity mediated by the CF 3 -pyridinyl group leaves us with a curiosity to investigate underlying ligand-binding mechanisms and dynamics using computational methods. Presented in this study are insights that clearly explain the effects of structural SF 5 -aniline!CF 3pyridinyl modifications on pfDHODH inhibition. Findings showed that the CF 3 -pyridinyl group induced an optimal and stabilized positioning of DSM421 within the binding pocket, allowing for steady and strong intermolecular interactions which favored its stronger binding affinity as estimated and correlated with bioactivity data. These interactions consequently induced a pronounced stabilization of the structural conformation of pfDHODH by restricting residue motions, which possibly underpinned its enhanced inhibitory activity relative to DSM265. Active site interactions of the CF 3 -pyrinidyl group with residues Ser236, Ile237, and Phe188 characterized by strong π -π stacking and halogen interactions also stabilized its positioning which altogether accounted for its enhanced inhibitory prowess towards pfDHODH. On the contrary, fewer and weaker interactions characterized DSM265 binding which could explain its relatively lower binding affinity. Findings will facilitate the design of novel pfDHODH inhibitors with enhanced properties.

Identification of potential SARS-CoV-2 inhibitors from South African medicinal plant extracts using molecular modelling approaches

“…The unbound 3CL pro conformation exhibited a relatively higher average ROG of 22.16Å while the arabic acid bound conformation exhibited lower of average ROG of 22.13Å. Radius of gyration of the c-α atoms of a protein correlated with protein compactness where a lower ROG is consistent with a compact structural conformation ( Labanov, 2008 , Agoni et al, 2019 , Agoni et al, 2020 ). As such, the relatively lower average ROG of arabic acid bound 3CL pro suggests a tight of compact enzyme conformation, consistent with the relatively stable system as observed in the RMSD calculation.…”

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] .…”

Dual‐Knockout of Mutant Isocitrate Dehydrogenase 1 and 2 Subtypes Towards Glioma Therapy: Structural Mechanistic Insights on the Role of Vorasidenib

“…We further assessed the stability of AG‐881 within the binding pockets of both m IDH1 and m IDH2, since this could influence the interaction dynamic course of AG‐881 [49,50] . Ligand stability could be influenced by the particular orientation that the ligand exhibits within a respective binding pocket [51–53] . We therefore assessed the binding modes/orientation of AG‐881 across the 300 ns MD simulations period.…”

“…Flexibility or mobility of amino acid residues surrounding the active site of m IDH1 and m IDH2 could also be used as a tool to predict the inhibitory impact of AG‐881 when bound to m IDH1 and m IDH2 [63,64] . As such, a root mean square fluctuation plot (RMSF) was generated for both mutant enzymes in their bound and unbound systems [65–67] .…”