Biology subjects

Malek, S.

Publications and source records attributed to Malek, S..

4 recordsLinked to original sources

bioRxiv2025

Computational Evaluation of Phytochemicals as Potential Anti-HIV Drugs Targeting CCR5 and CXCR4 Receptors

HIV is a major worldwide health concern; hence new therapeutic approaches are needed to fight viral resistance and enhance treatment results. HIV entrance into host cells depends on the CCR5 and CXCR4 receptors, which makes them potential targets for antiviral medication development. The objective of this study is to computationally evaluate 53 phytochemicals that target CCR5 and CXCR4 as potential anti-HIV medications. Effective anti-HIV medications were projected to be phytochemicals that may inhibit these receptors and so interfere with the HIV life cycle. AutoDock Vina was used to perform the molecular docking investigation from which six phytochemicals capable of inhibiting CCR5 and CXCR4 were identified based on the lowest docking score. i.e., Withaferin A, Oleanolic Acid, Ursolic Acid, Theaflavine, Camptothecin, and Hypericin. The SWISSADME server was utilized to decide their druglikeness properties, the ADMETlab server to predict different pharmacokinetic and pharmacodynamic properties, the PASS-Way2Drug server to evaluate their activity spectra, and the RS-WebPredictor server to figure out the metabolism in the body. They adhered to Lipinskis rule of five and had promising ADME/toxicity study result along with favorable molecular dynamics simulation. Overall, the above-mentioned six phytochemicals might have the potential to be used as alternative HIV therapeutics.

bioinformatics↗

bioRxiv2023

Targeting the Hippo pathway in cancers via ubiquitination dependent TEAD degradation

The Hippo pathway is among the most frequently altered key signaling pathways in cancer. TEAD1-4 are essential transcription factors and key downstream effectors in the Hippo pathway in human cells. Here, we identified RNF146 as a ubiquitin ligase (E3) of TEADs, which negatively regulates their stability in cells through proteasome-mediated degradation. We show that RNF146-mediated TEAD ubiquitination is dependent on the TEAD PARylation state. We further validated the genetic interaction between RNF146 and the Hippo pathway in cancer cell lines and the model organism Drosophila melanogaster. Despite the RNF146 and proteasome-mediated degradation mechanisms, TEADs are stable proteins with a long half-life in cells. We demonstrate that degradation of TEADs can be greatly enhanced pharmacologically with heterobifunctional chemical inducers of protein degradation (CIDEs). These TEAD-CIDEs can effectively suppress activation of YAP/TAZ target genes in a dose-dependent manner and exhibit significant anti-proliferative effects in YAP/TAZ-dependent tumor cells, thus phenocopying the effect of genetic ablation of TEAD protein. Collectively, this study demonstrates that the ubiquitin-proteasome system plays an important role in regulating TEAD functions and provides a proof-of-concept demonstration that pharmacologically induced TEAD ubiquitination could be leveraged to target YAP/TAZ-driven cancers.

cancer biology↗

bioRxiv2022

Impact of long-term storage on mid-infrared spectral patterns of serum and synovial fluid samples of dogs with osteoarthritis

ObjectiveTo evaluate impact of long-term storage on mid-infrared (MIR) spectral patterns of serum and synovial fluid (SF) of dogs with knee OA and controls. DesignSerum (52 OA and 49 control) and SF (51 OA and 51 control) samples from dogs that had been in short-term (<3 years) frozen state (-80{degrees}C) had their MIR spectra obtained. The remaining aliquots were maintained in long-term (>5 years) frozen state before having MIR spectra acquired under the same testing conditions. Multi-level simultaneous component analysis was used to evaluate the effect of time. Partial least squares discriminant analysis was used to compare performance of predictive models built for discriminating OA from control spectra from each time point. ResultsMedian interval of storage between sample measurements was 5.7 years. Spectra obtained at two time points were significantly different (P <0.0001), however, contribution of sample aging accounted for only 1.61% and 2.98% of serum and SF profiles variability, respectively. Predictive models for discriminating serum of OA from controls for short-term storage showed 87.3{+/-}3.7% sensitivity, 88.9{+/-}2.4% specificity and 88.1{+/-}2.3% accuracy, while, for long-term storage, values of the same figures of merit were 92.5{+/-}2.6%, 97.1{+/-}1.7% and 94.8{+/-}1.4%, respectively. Predictive models based on short-term stored SF spectra had 97.3{+/-}1.6% sensitivity, 89.4{+/-}2.6% specificity and 93.4{+/-}1.6% accuracy, while the values for long-term storage 95.7{+/-}2.1%, 95.7{+/-}0.8% and 95.8{+/-}1.1%, respectively. ConclusionsLong-term storage of serum and SF results in significant differences in spectral variables, however, these changes do not significantly alter the performance of predictive algorithms for discriminating OA samples from controls.

biochemistry↗

bioRxiv2021

RTK-dependent inducible degradation of mutant PI3K alpha drives GDC-0077 (Inavolisib) efficacy

PIK3CA is one of the most frequently mutated oncogenes; the p110 protein it encodes plays a central role in tumor cell proliferation and survival. Small molecule inhibitors targeting the PI3K p110 catalytic subunit have entered clinical trials, with early-phase GDC-0077 (Inavolisib) studies showing anti-tumor activity and a manageable safety profile in patients with PIK3CA-mutant, hormone receptor-positive breast cancer as a single agent or in combination therapy. Despite this, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression, resulting in enhanced apoptosis and greater efficacy. This unique mechanism against mutant p110 reveals a new strategy for creating inhibitors that specifically target mutant tumors with selective degradation of the mutant oncoprotein and also provide a strong rationale for pursuing PI3K degraders in patients with HER2-positive breast cancer.

cancer biology↗