Biology subjects

Dogru, S.

Publications and source records attributed to Dogru, S..

4 recordsLinked to original sources

bioRxiv2026

Quantitative Systems Pharmacology Model for Trop-2 Targeting Antibody-Drug Conjugate in Triple-Negative Breast Cancer

TROP2-targeted antibody-drug conjugates (ADCs) have demonstrated promising clinical activity in triple-negative breast cancer (TNBC) as monotherapies; however, therapeutic benefit varies among patients. Combination strategies pairing TROP2-targeted ADCs with immune checkpoint inhibitors are also being investigated. Elucidating the mechanistic drivers of ADC monotherapy variability and enabling the rational development of combination regimens require computational frameworks that integrate ADC pharmacology with tumor-immune interactions. A quantitative systems pharmacology (QSP) model is presented that incorporates an ADC module into our established immuno-oncology model for TNBC. The module captures ADC and payload pharmacokinetics and pharmacodynamics. TNBC heterogeneity is represented by two tumor cell clones with high and low TROP2 expression, informed by prior characterizations, and differential sensitivity to the ADC payload is incorporated as an intrinsic property of each clone. Although generalizable, the model was applied to the TROP2-targeted ADC sacituzumab govitecan (SG, TRODELVY). A virtual patient cohort was generated using Latin hypercube sampling and calibrated against objective response rate (ORR) data from SG Phase I/II TNBC basket trial. The model predicted an ORR of 33.2% consistent with ASCENT study (NCT02574455). Simulations suggest TROP2-mediated delivery contributes modestly to SG efficacy with tumor exposure driven largely by systemically released SN-38 payload being sufficient to induce cytotoxicity. Tumor heterogeneity emerged as a key determinant of response with ORR increasing as the fraction of payload-sensitive clones increased. Overall, this QSP framework for TROP2-targeted ADCs accounts for TNBC heterogeneity and is extendable to other ADCs and targets enabling interrogation of ADC mechanisms of action in conjunction with tumor-immune interactions.

pharmacology and toxicology↗

bioRxiv2026

The Cytochrome b m.14849T>C (S35P) Variant Induces Structural and Dynamic Alterations in the Heme bL Microenvironment in Multisystem Disease

Mitochondrial Complex III dysfunction is frequently associated with pathogenic variants in the MT-CYB gene, yet the functional consequences of many missense substitutions remain unresolved because they are classified as variants of uncertain significance (VUS). One such variant, m.14849T>C (p.Ser35Pro), has been reported in patients with multisystem mitochondrial phenotypes, including septo-optic dysplasia, cardiomyopathy, and exercise intolerance, although its structural impact on Cytochrome b function remains unclear. In this study, we employed 300 ns all-atom molecular dynamics simulations to assess structural and energetic consequences of the S35P substitution in the Cytochrome b subunit of human mitochondrial Complex III. The S35P variant did not induce global destabilization of the protein scaffold but instead promoted localized perturbations within the heme bL microenvironment. The mutation was associated with loss of a heme-proximal hydrogen-bonding network involving Ser35 and a decrease in electrostatic interaction energy between the protein matrix and the heme bL cofactor. Radial distribution function analysis further supported loosening of local packing around the prosthetic group. Consistent with these local changes, dynamics analyses indicated increased flexibility in distal transmembrane helices that form the heme-pocket scaffold and greater variability in the inter-heme Fe(bL)-Fe(bH) distance. Together, our findings suggest that S35P may exert functional effects by reorganizing the heme bL microenvironment rather than by inducing large-scale structural destabilization, underscoring the value of structure- and dynamics-based evaluation for mitochondrial VUS and suggesting a plausible mechanistic link to the pathophysiology of multisystem mitochondrial diseases.

biophysics↗

bioRxiv2025

Angiotensin 1-7 Modulates the Dynamics and Activation of the Proto-oncogene Mas Receptor

The proto-oncogene Mas receptor (MasR, UniProt ID: P04201) is a class-A (orphan-type) G protein-coupled receptor (GPCR) that mediates the protective effects of Angiotensin 1-7 (Ang 1-7) within the renin-angiotensin system (RAS). Despite its therapeutic relevance, the molecular mechanisms underlying MasR activation by Ang 1-7 remain elusive due to the lack of experimental structural data. In this study, we performed 1-microsecond all-atom molecular dynamics (MD) simulations of AlphaFold-modeled active and inactive MasR conformations, with and without Ang 1-7, to characterize ligand-induced conformational dynamics. Ang 1-7 binding led to increased interaction stability in the active state, reflected by higher occupancy of hydrogen bonds, salt bridges, and hydrophobic contacts. Structural analyses revealed reduced RMSD/RMSF values and stabilization of key transmembrane (TM) helices and the NPxxY micro-switch. TM distance and dihedral analyses indicated partial TM6 displacement and time-dependent NPxxY reorganization. Network-based metrics including betweenness centrality and shortest path length highlighted the emergence of state-specific communication hubs, while PCA, correlation and communication propensity analyses revealed enhanced conformational diversity and selective inter-residue signaling in the ligand-bound state. Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations showed favorable binding energetics in the active state ({Delta}GBind = -13.99 kcal/mol). These results demonstrate that Ang 1-7 acts as a partial agonist of MasR by stabilizing the inactive conformation while inducing limited activation features in the active state through non-canonical micro-switch dynamics. This work advances structural insights into MasR regulation and provides a foundation for therapeutic targeting of the ACE2/Ang 1-7/MasR axis.

biophysics↗

bioRxiv2023

Physiologic Doses of TGF-beta Improve the Composition of Engineered Articular Cartilage

For cartilage regeneration applications, transforming growth factor beta (TGF-{beta}) is conventionally administered at highly supraphysiologic doses (10-10,000 ng/mL) in an attempt to cue cells to fabricate neocartilage that matches the composition, structure, and functional properties of native hyaline cartilage. While supraphysiologic doses enhance ECM biosynthesis, they are also associated with inducing detrimental tissue features, such as fibrocartilage matrix deposition, pathologic-like chondrocyte clustering, and tissue swelling. Here we investigate the hypothesis that moderated TGF-{beta} doses (0.1-1 ng/mL), akin to those present during physiological cartilage development, can improve neocartilage composition. Variable doses of media-supplemented TGF-{beta} were administered to a model system of reduced-size cylindrical constructs (O2-O3 mm), which mitigate the TGF-{beta} spatial gradients observed in conventional-size constructs (O4-O6 mm), allowing for a novel assessment of the intrinsic effect of TGF-{beta} doses on macroscale neocartilage properties and composition. The administration of physiologic TGF-{beta} to reduced-size constructs yields neocartilage with native-matched sGAG content and mechanical properties while providing a more hyaline cartilage-like composition, marked by: 1) reduced fibrocartilage-associated type I collagen, 2) 77% reduction in the fraction of cells present in a clustered morphology, and 3) 45% reduction in the degree of tissue swelling. Physiologic TGF-{beta} appears to achieve an important balance of promoting requisite ECM biosynthesis, while mitigating hyaline cartilage compositional deficits. These results can guide the development of novel physiologic TGF-{beta}-delivering scaffolds to improve the regeneration clinical-sized neocartilage tissues.

bioengineering↗