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

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 SF₅‐aniline group on DSM265 with a CF₃‐pyridinyl moiety. Consequently, DSM421 exhibited improved pharmacological and pharmacokinetics attributes relative to DSM265. The improved bioactivity mediated by the CF₃‐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 SF₅‐aniline→CF₃‐pyridinyl modifications on pfDHODH inhibition. Findings showed that the CF₃‐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 CF₃‐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.     

A dual target of Plasmepsin IX and X: Unveiling the atomistic superiority of a core chemical scaffold in malaria therapy

Plasmepsin IX and X, members of the prominent aspartic family of proteases whose function were hitherto unknown have only recently been established as key mediators of erythrocyte invasion and egress of the virulent malarial parasite. Inhibitor 49c, a potent antimalarial peptidomimetic inhibitor initially developed to target Plasmepsin II has lately been proven to exhibit potent inhibitory activity against Plasmepsin IX and X. However, the molecular and structural dynamics supporting its inhibitory activity remain inconclusive. Hindering the motion of the flap and hinge region of an aspartic protease remains essential for disabling the catalytic activity of the enzyme. Integrating molecular dynamic simulations coupled with other advanced biocomputational tools, we reveal the enhanced structural mechanistic competence of 49c in complex with Plasmepsin IX and X relative to Pepstatin. Pepstatin, a known aspartic protease inhibitor which actively hinders the opening and closing of the flap tip and flexible loop and consequently limits access to the catalytic aspartic residues, however, its administration has been related to elevated levels of toxicity. Thermodynamic calculations reveal a higher relative binding free energy associated with Plasmepsin IX and X in complex with 49c as opposed to Pepstatin. A relatively compact and structurally rigid 49c bound complexes sequel into the restriction of the flap and hinge residues by restraining cohesive movement, consequently hindering their “twisting motion” from transpiring. Findings unveil an atomistic perspective into the structural superiority of 49c in complex with Plasmepsin IX and X.     

Combined stable‐isotope and fatty‐acid analyses demonstrate that large wood increases the autochthonous trophic base of a macroinvertebrate assemblage

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5-Azacytidine as a tool to induce somaclonal variants with useful traits in sugarcane (Saccharum spp.)

A possible strategy to produce variant sugarcane plants with beneficial traits was tested by promoting somaclonal variation in vitro through the action of the hypomethylation and mutagenic agent 5-Azacytidine (Azac). Treatment of calli in liquid medium caused high levels of necrosis. Consequently, 6- to 8-week-old calli of cultivar NCo376 were exposed to 50 and 100 μM Azac in semi-solid callus induction medium (CIM) (MS salts and vitamins, sucrose, casein hydrolysate, agar, with or without 3 mg l^?1 2,4-D) for 1 week. They were then transferred to fresh CIM with 2,4-D and to CIM without 2,4-D, for 2 and 8–10 weeks, respectively. The highest callus necrosis (>60 %) and reduced recovery (<40 %) were recorded for calli treated with 100 μM Azac without 2,4-D, which also resulted in lower plant yield (12 plantlets/0.2 g calli) than the control (18 plantlets/0.2 g calli). From methylation-sensitive amplified fragment length polymorphism analyses, the highest polymorphisms (4.2 %) were also obtained from plants derived from the 100 μM Azac treatment without 2,4-D. After 9 months of field growth, Azac-derived plants exhibited phenotypic differences compared with the controls. Ex vitro screening resulted in the identification of one plant from the 100 μM Azac with 2,4-D treatment putatively tolerant to smut, and three plants from the 100 μM Azac with 2,4-D and one from the 50 μM Azac with 2,4-D treatments, potentially tolerant to the herbicide imazapyr.     

Dietary changes in predators and scavengers in a nocturnally illuminated riparian ecosystem

Aquatic and terrestrial ecosystems are linked by fluxes of carbon and nutrients in riparian areas. Processes that alter these fluxes may therefore change the diet and composition of consumer communities. We used stable carbon isotope (δ¹³C) analyses to test whether the increased abundance of aquatic prey observed in a previous study led to a dietary shift in riparian consumers in areas illuminated by artificial light at night (ALAN). We measured the contribution of aquatic‐derived carbon to diets in riparian arthropods in experimentally lit and unlit sites along an agricultural drainage ditch in northern Germany. The δ¹³C signature of the spider Pachygnatha clercki (Tetragnathidae) was 0.7‰ lower in the ALAN‐illuminated site in summer, indicating a greater assimilation of aquatic prey. Bayesian mixing models also supported higher intake of aquatic prey under ALAN in spring (34% versus 21%). In contrast, isotopic signatures for P. clercki (0.3‰) and Pardosa prativaga (0.7‰) indicated a preference for terrestrial prey in the illuminated site in spring. Terrestrial prey intake increased in spring for P. clercki under ALAN (from 70% to 74%) and in spring and autumn for P. prativaga (from 68% to 77% and from 67% to 72%) and Opiliones (from 68% to 72%; 68% to 75%). This was despite most of the available prey (up to 80%) being aquatic in origin. We conclude that ALAN changed the diet of riparian secondary consumers by increasing the density of both aquatic and terrestrial prey. Dietary changes were species‐ and season‐specific, indicating that the effects of ALAN may interact with phenology and feeding strategy. Because streetlights can occur in high density near freshwaters, ALAN may have widespread effects on aquatic–terrestrial ecosystem linkages.