Yasar, Ekrem; Dogru, Segun; Eroglu, Erol; Yaras, Nazmi

The proto-oncogene Mas receptor (MasR) is a class-A (orphan-type) G protein-coupled receptor (GPCR) that mediates the cardioprotective effects of Angiotensin 1–7 (Ang 1–7) within the renin–angiotensin system (RAS). Despite its therapeutic relevance, the molecular mechanisms underlying MasR activation remain elusive due to the lack of experimental structural data. In this study, we combined 1-μs all-atom molecular dynamics (MD) simulations of AlphaFold-modeled MasR with energetic network analyses to elucidate ligand-induced activation dynamics. Our results challenge the conventional electrostatic clamp model, revealing a distinct active anchor mechanism. We demonstrate that Ang 1–7 releases the inactive core lock (ARG245–TYR248) to engage a critical anchor cluster (SER109/PHE112). This interaction stabilizes a unique decoupled conformational state: while the NPxxY motif is fully activated and the intracellular vestibule expands via noncanonical communication hubs that substitute for the absent conserved microswitches, TM6 remains in a restricted, compact conformation (~10 Å). Thermodynamically, this partial activation is supported by favorable computed binding energetics and enhanced conformational plasticity. These findings provide a structural rationale for the partial agonist profile of Ang 1–7 and offer a transformative mechanistic framework for therapeutic targeting of the ACE2/Ang 1–7/MasR axis. We propose that rational drug design need not aim for maximal receptor opening; instead, strategies focusing on peptidomimetics or positive allosteric modulators (PAMs) that stabilize this specific compact active state could selectively potentiate protective RAS signaling.

Türkeş, Cüneyt

Enzyme inhibition is a commonly utilized method for controlling enzymatic activity in various physiologically relevant biological systems. Herein, the selected five active antiviral drugs, abacavir, emtricitabine, lamivudine, ribavirin, and ritonavir, were assayed as inhibitors of two human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) involved in various physiological/pathological conditions. For this aim, in vitro and in silico studies were performed to gain insights into the plausible binding interactions and affinities for the antiviral drugs within hCA I and II isoforms' active sites. The hCA I, an isoform involved in some pathological conditions such as retinal or cerebral edema, was moderately inhibited by these five drugs at micromolar concentrations with KIs spanning from 0.49 ± 0.05 to 3.51 ± 0.37 μM compared with the reference drug acetazolamide (AAZ, KI of 0.19 ± 0.01 μM). Moreover, hCA II, a promising target for edema, glaucoma, epilepsy, and altitude sickness, was a reasonably inhibited isoform by these agents, with KIs in the range of 0.64 ± 0.08–5.80 ± 0.64 μM compared with AAZ (KI of 0.17 ± 0.01 μM). Both in vitro and in silico results demonstrated significant interactions between these five drugs and hCAs and that they can support therapeutic targets against the above-mentioned pathological conditions. Additionally, the results obtained will help optimize the clinical dosage regimens of these drugs and avoid drug–drug interactions unexpectedly when used in combination with other agents.

Türkeş, Cüneyt; Arslan, Mustafa; Demir, Yeliz; Çoçaj, Liridon; Nixha, Arleta Rifati; Beydemir, Şükrü

Aldose reductase (AR, AKR1B1; EC 1.1.1.21) is an aldo-keto reductase that has been widely investigated as an enzyme crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although sulfonamides have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR, herein, we have evaluated the AR inhibitory potential of N-substituted phthalazine sulfonamide derivatives 5a-l. The biological studies revealed that all the derivatives show excellent activity against AR, with KI constants ranging from 67.73 to 495.20 nM. Among these agents, 4-(6-nitro-1,4-dioxo-1,2,3,4-tetrahydrophthalazine-2-carbonyl)benzenesulfonamide (5e) and 1,4-dioxo-3-(4-sulfamoylbenzoyl)-1,2,3,4-tetrahydrophthalazine-6-carboxylic acid (5f) showed prominent inhibitory activity with KI values of 67.73 and 148.20 nM, respectively, vs AR and were found to be more potent than epalrestat (KI = 852.50 nM), the only AR inhibitor currently used in the therapy. Moreover, molecular docking studies were also performed to rationalize binding site interactions of these sulfonamides (5a-l) with the target enzyme AR. According to ADME-Tox, predicts were also determined that these derivatives be ARIs displaying suitable drug-like properties. The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications.