Biology subjects

Elokely, K.

Publications and source records attributed to Elokely, K..

4 recordsLinked to original sources

bioRxiv2026

Interfacial water in the PRDX1-sulfiredoxin repair intermediate: an all-atom molecular dynamics study

Peroxiredoxins protect cells from oxidative damage, and sulfiredoxin (Srx) restores their activity by repairing the overoxidized catalytic cysteine; how the two proteins recognize one another is central to redox signaling and to oxidative-stress-associated disease. We characterize the human peroxiredoxin-1 (PRDX1)-Srx repair intermediate (PDB 2RII) and four related catalytic-cysteine states by all-atom molecular dynamics (three replicas of 200 ns per system; 3.0 microsecond total), using geometric and kinetic observables only, with across-replica statistics. The disulfide-linked complex is stable (backbone RMSD 2.5- 3.2 Angstrom) and the peroxidatic Cys52 is buried in the interface (buried surface area 71-76 Angstrom^2). The interface is extensive, with 202 consensus residue-residue contacts, and predominantly water-mediated: 20 reproducible, hydrogen-bond-validated water bridges centered on the PRDX1 165-170 region, against three persistent salt bridges. Removing the engineered tether and modeling Cys52 as the sulfinate on which Srx acts leaves the interface intact (189 consensus contacts) and the water network larger (36 bridges), new bridges linking the sulfinate to the Srx catalytic pocket. At the free Cys52, first-shell water responds to charge state as electrostatics predicts, and at matched water counts the thiolate shows no additional clustering, separating generic hydration from the specific interfacial organization. An equalized, permutation-controlled comparison of the Srx-bound and free intra-PRDX1 contact networks leaves them statistically indistinguishable: of 14,127 residue pairs only one exceeds both floors, and it does not reproduce across independent trajectory sets. A covalent celastrol-Cys173 adduct retains its thioether bond while the tethered ligand reorients widely, so covalent attachment fixes the anchor rather than the pose.

pharmacology and toxicology↗

bioRxiv2026

Molecular size dominates α2-adrenergic subtype-selectivity benchmarks: five controls for reducing attrition in selective ligand design

Background: Subtype-selectivity predictions are scored against measured selectivity and judged against an assumed noise ceiling. We asked what an 2-adrenergic benchmark rewards and which controls change its interpretation. Research design and methods: On a frozen benchmark of 586 paired 2A/2C compounds we evaluated Glide SP docking, CNN rescoring, ligand-only fingerprint models, receptor descriptors and pose contacts, with dopamine D3/D2 as comparator, applying five controls: a measured ceiling, a cluster-identity null, a nonselective reference, a same-receptor floor and a trivial-descriptor baseline. Results: Five descriptors from SMILES reached Spearman 0.645, 72% of the measured ceiling, against 0.071 for Glide SP and 0.188 for CNN rescoring; receptor properties and pose contacts reduced to size under control, while a non-size signal of 0.258 survived. Measured rather than propagated noise raised that ceiling from 0.704 to 0.897; cluster identity alone reached R2 0.499 on D3/D2 and none on 2; a nonselective reference received +1.43 to +4.79 kcal/mol where zero is expected; and a same-receptor floor reached 1.77-fold against 1.88-fold across subtypes. Conclusions: Such benchmarks reward molecular size first; a method must exceed 0.645 before its score indicates structural reasoning. The controls are inexpensive; conclusions rest on two receptor pairs, a three-pair floor and static structures.

pharmacology and toxicology↗

bioRxiv2026

An Exact-Residue Atlas of Opioid Receptor Wiring and Rewiring across Ligand and Transducer Contexts

Opioid-receptor structures span four human receptor subtypes, diverse ligands, signaling partners, and experimental constructs. We curated 86 human opioid-receptor structures representing 84 independent experimental maps, with one unique experimental data set counted once for structure-level inference, and analyzed them using our in-house StrucMind platform. StrucMind constructs exact Ballesteros-Weinstein (BW) contact graphs, meaning residue-contact networks restricted to unambiguous generic BW positions. Relative to active transducer-bound structures, structures classified as inactive showed 2.49% lower mean contact similarity and 34.84% more rewired contacts, where rewiring is the static set of contacts gained or lost between two structures. Among 77 maps with a resolved selected-ligand site, changed contacts were 15.28% direct to the site, 40.13% adjacent at one graph edge, and 44.59% connected-distal at a finite graph distance greater than one. The deposited-water analysis identified 137 receptor-proximal waters. Sixty-one contacted at least two protein residues, including 38 that bridged at least two exact-BW residues; a separate ligand-contact branch contained 10 waters contacting both selected ligand and receptor, only 3 of which belonged to the 38-water set. None of 32 component-association tests survived global correction. For peptide versus small molecule, the smallest nominal p value among four outcomes corresponded to 6.18% lower shared-contact distance root-mean-square deviation (p=0.00989; q=0.3165, where q is the adjusted p value). The atlas supports bounded, testable hypotheses, not causal component, hydration, or efficacy mechanisms.

bioinformatics↗

bioRxiv2021

Selective inhibition of PfATP6 by artemisinins and identification of new classes of inhibitors after expression in yeast

Treatment failures with artemisinin combination therapies (ACTs) threaten global efforts to eradicate malaria. They highlight the importance of identifying drug targets and new inhibitors and of studying how existing antimalarial classes work. Herein we report the successful development of an heterologous expression-based compound screening tool. Validated drug target P. falciparum calcium ATPase6 (PfATP6) and a mammalian ortholog (SERCA1a) were functionally expressed in yeast providing a robust, sensitive, and specific screening tool. Whole-cell and in vitro assays consistently demonstrated inhibition and labelling of PfATP6 by artemisinins. Mutations in PfATP6 resulted in fitness costs that were ameliorated in the presence of artemisinin derivatives when studied in the yeast model. As previously hypothesised, PfATP6 is a target of artemisinins. Mammalian SERCA1a can be mutated to become more susceptible to artemisinins. The inexpensive, low technology yeast screening platform has identified unrelated classes of druggable PfATP6 inhibitors. Resistance to artemisinins may depend on mechanisms that can concomitantly address multi-targeting by artemisinins and fitness costs of mutations that reduce artemisinin susceptibility.

pharmacology and toxicology↗