Biology subjects

Perez-Sanchez, H.

Publications and source records attributed to Perez-Sanchez, H..

8 recordsLinked to original sources

bioRxiv2026

AgamOBP4-targeted drug repurposing identifies novel mosquito repellent scaffolds

Odorant-binding proteins (OBPs) play central roles in insect chemoreception and represent attractive molecular targets for the discovery of novel behavior-modifying compounds. We report two crystal structures of Anopheles gambiae OBP4: one complexed with the fluorescent probe N-phenyl-1-naphthylamine and a second containing two indole molecules simultaneously bound within the ligand-binding cavity. Structural comparison revealed two binding subsites accommodating the aromatic moieties of 1-NPN or two indole molecules, while identifying Thr58 and Thr70 as key residues in ligand recognition. A structure-based virtual screening campaign was performed against a volatility-filtered library from DrugBank, FooDB, BioNet, and natural-volatiles datasets. Twenty-three ligands were selected for fluorescence competitive binding assays, identifying four AgamOBP4 binders with micromolar affinities (Ki = 2.4-21.8 M). Among them were benzoyl peroxide, an active anti-acne ingredient, Avex-73 (blarcamesine), a clinical-stage drug candidate, and 2-phenylethyl benzoate, a food- and fragrance-associated ester. Additional candidates include O,p'-DDE, a metabolite of the insecticide DDT, and fluorene, a polycyclic aromatic hydrocarbon detected in foods as environmental or processing-derived contaminants. Seven selected compounds were subsequently evaluated against Aedes albopictus in in-vivo behavioral assays, with benzoyl peroxide displaying the highest repellency (RI = 81.8% at 0.2 mg cm-2). AI-based protein-ligand modeling provided insights into ligand recognition and suggested relationships among binding mode, binding affinity, and bioactivity. Collectively, these findings establish the structural basis of ligand recognition by AgamOBP4, highlight the potential of drug-repurposing and food-derived chemical space as sources of next-generation mosquito repellents, and open new opportunities for the development of OBP4-based biosensors for food-quality and environmental monitoring applications.

biochemistry↗

bioRxiv2025

Characterizing Compounds Targeting Colorectal Cancer Derived From Monastrol Using High-Through Screening of an Extensive Combinatorial Library

BackgroundCancer remains a critical global health concern. Among its various forms, colorectal cancer (CRC) stands out due to its high prevalence and mortality rates, emphasizing the urgent need for novel therapeutic agents to enhance treatment efficacy and prolong patient survival. Monastrol, an antimitotic compound known to bind kinesin Eg5, is employed in some cancer therapies. Recent studies have revealed that monastrol also interacts with fascin, a protein implicated in tumor aggressiveness and metastasis, thereby disrupting microtubule dynamics and actin bundling, ultimately impairing cell migration. MethodsIn this work, we developed a workflow to identify fascin-binding compounds based on a monastrol-derived pharmacophore model, integrating in silico predictions with in vitro validation. We performed ligand-based virtual screening using a pharmacophore model constructed from monastrol, applied to a high-throughput screening (HTS) library of 1.6 million compounds. The top-ranking candidates from the virtual screening were subsequently subjected to physicochemical characterization and cellular assays. ResultsTwo compounds (designated Z118298144 and Z17544625) were identified that exhibited strong binding to fascin and inhibited actin bundling in physicochemical assays. Furthermore, cellular experiments demonstrated that both compounds reduced proliferation and impaired migration of CRC cells at micromolar concentrations. ConclusionsWe established an optimized pipeline combining virtual screening with experimental validation to efficiently identify fascin inhibitors. Using this approach, we discovered two promising compounds with anticancer activity in CRC cell cultures. Moreover, the protocol has been successfully adapted for application to additional cancer-related targets, expanding its potential utility in drug discovery. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/667829v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@dc470eorg.highwire.dtl.DTLVardef@1bd0759org.highwire.dtl.DTLVardef@12d755dorg.highwire.dtl.DTLVardef@1742d45_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

OBE-DB: A Computational Tool and Web Server for the Prediction of Antiobesity Drugs

The huge obesity prevalence and its associated metabolic disorders highlight the urgent need for new therapeutic strategies beyond lifestyle interventions. Despite the availability of novel pharmacological treatments, the search for more effective and safe anti-obesity compounds remains a challenge. Recent advances in high-performance computational drug discovery have enabled the rapid screening and identification of potential anti-obesity compounds. However, these in silico procedures frequently require complex computational knowledge that limits the use of these techniques for most researchers. To address this gap, we have developed OBE-DB, an accessible and user-friendly platform integrating these computational tools that facilitates the prediction of potential anti-obesity molecules through two complementary approaches: (a) shape similarity analysis against a curated database of approved anti-obesity drugs, and (b) inverse virtual screening of user-submitted molecules against a set of therapeutic protein targets linked to obesity. Our results demonstrate that the server effectively screens and ranks compounds with high predicted activity, outperforming conventional in silico techniques in terms of accuracy and usability. This represents a significant advancement by providing researchers with an intuitive tool to accelerate early-stage drug discovery for obesity treatment. The server is freely accessible without registration, providing users with a detailed report via email upon completion of the predictions. This innovative database and web server is accessible online via http://bio-hpc.eu/software/obe-db/.

bioinformatics↗

bioRxiv2024

Exploring the druggability of the UEV domain of human TSG101 in search for broad-spectrum antivirals

The ubiquitin E2 variant domain of TSG101 (TSG101-UEV) plays a pivotal role in protein sorting and virus budding by recognizing PTAP motifs within ubiquitinated proteins. Disruption of TSG101-UEV/PTAP interactions has emerged as a promising strategy for the development of host-oriented broad-spectrum antivirals with low susceptibility to resistance. TSG101 is a challenging target characterized by an extended and flat binding interface, low affinity for PTAP ligands, and complex binding energetics. Here, we assess the druggability of the TSG101-UEV/PTAP binding interface by searching for drug-like inhibitors and evaluating their ability to block PTAP recognition, impair budding, and inhibit viral proliferation. A discovery workflow was established combining in vitro miniaturized HTS assays and a set of cell-based activity assays including high-content bimolecular complementation, virus-like particle release measurement, and antiviral testing in live virus infection. This approach has allowed us to identify a set of chemically diverse molecules that block TSG101-UEV/PTAP binding with IC50s in the low M range, and able to disrupt the interaction between full-length TSG101 and viral proteins in human cells and inhibit viral replication. State-of-the-art molecular docking studies reveal that the active compounds exploit binding hotspots at the PTAP binding site, unlocking the full binding potential of the TSG101-UEV binding pockets. These inhibitors represent promising hits for the development of novel broad-spectrum antivirals through targeted optimization and are also valuable tools for investigating the involvement of ESCRT in the proliferation of different virus families and study the secondary effects induced by the disruption of ESCRT/virus interactions. ImportanceMany viruses rely on the interaction between TSG101 and viral proteins containing PTAP motifs for their proliferation. Here we show that these interactions can be efficiently blocked by drug-like compounds that impair budding and replication of viruses from different families. We have also provided valuable insights into the determinants of high affinity for these small molecule inhibitors that open new avenues for developing the identified candidates into broad-spectrum antivirals with low susceptibility to resistance.

molecular biology↗

bioRxiv2024

Discovery of Z1362873773: A Novel Fascin Inhibitor from a Large Chemical Library for Colorectal Cancer

Metastasis is one of the leading causes of cancer-related death worldwide. Fascin is involved in this process by bundling actin filaments and producing protrusions in cancer cells, which facilitate their migration. It has been shown that the overexpression of this protein is related to the appearance of different types of cancer, such as colorectal cancer. In this study, we conducted an in silico screening against the enamine library, a compound library with a broad chemical space ({approx}1.4M compounds), followed by further validation with physicochemical assays and cellular migration and cytotoxicity tests, thereby obtaining a molecule with considerable fascin inhibitory and migration-arresting capacity similar to other inhibitors already known in the literature. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/606007v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@10ddb2borg.highwire.dtl.DTLVardef@afe8b1org.highwire.dtl.DTLVardef@d5f436org.highwire.dtl.DTLVardef@940ddc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Pro-tumor and prothrombotic activities of hepsin in colorectal cancer cells and suppression by venetoclax

Hepsin is a type II transmembrane serine protease whose expression has been linked to greater tumorigenicity and worse prognosis in different tumors such as prostate and gastric cancer. Recently, our group described hepsin expression in the primary biopsy as a potential biomarker of thrombosis and metastasis in localized colorectal cancer patients. Here we explored the role of hepsin in this tumor. Hepsin overexpression increased Caco-2 cell migration and invasion, higher phosphorylation of Erk1/2 and STAT3 and led to more thrombin generation in plasma. Indeed, our study revealed higher plasma levels of hepsin in metastatic colorectal cancer patients, which was associated with a greater tendency toward thrombosis. By virtual screening of a FDA-approved drug library, we identified venetoclax as a potent hepsin inhibitor, reducing the metastatic and prothrombotic phenotype of Caco-2 cells, but not of other colorectal cancer cells without hepsin expression. Interestingly, pre-treating Caco-2 cells overexpressing hepsin with venetoclax reduced its in vivo invasiveness. Taken together, our results demonstrate that elevated hepsin levels correlate with a more aggressive and prothrombotic tumor phenotype. Likewise, they evidence an antitumor role for venetoclax as a hepsin inhibitor. This lays the groundwork for molecular targeted therapy for colorectal cancer.

cancer biology↗

bioRxiv2021

A conserved role of Parkinson-associated DJ-1 metabolites in sperm motility, mitosis, and embryonic development

Fertility rates in the developing world have dramatically dropped in the last decades. This drop is likely due to a decline in sperm quality and women having children at older ages. Loss of function mutations in DJ-1, a Parkinsons associated gene, are linked to alterations in multiple cellular processes such as mitochondrial activity, ROS production or sperm motility and lead to an early onset of Parkinsons disease and male infertility in humans and other species. Glycolate (GA) and D-lactate (DL), products of DJ-1 glyoxalase activity, sustain mitochondrial function and protect against environmental aggressions. We, therefore, tested whether these substances could also have a rescue effect on these phenotypes. Here, we show that DJ-1 loss of function not only affects sperm motility but also leads to defects in mitosis and an age-dependent increase in the abortion rate. Remarkably, whereas DL was only able to rescue embryonic lethality in C. elegans, GA rescued these phenotypes in all model systems tested and even increased sperm motility in wild-type sperm. These positive effects seem to be mediated through an increase in NAD(P)H production and the regulation of intracellular calcium. These findings not only strongly suggest GA as a new therapeutic candidate to improve male and female fertility but also show its potential to treat diseases associated with a decline in mitochondrial function or to improve mitochondrial function in aging.

developmental biology↗

bioRxiv2016

Computational evidence of a compound with nicotinic α4β2-Ach receptor partial agonist properties as possible coadjuvant for the treatment of obesity

BackgroundNowadays, the search for new anti-obesity drugs is oriented to the use of anti-addiction medications like bupropion and naltrexone. Other compounds like varenicline may be also useful to treat obesity. However, the low effectiveness of the former or the high number of adverse effects of the latter makes it necessary to search for new therapeutic agents.\n\nMethodsScreening database selected for the computational experiments was DrugBank. 3D global shape comparison with varenicline was performed by means of the Ligand Based Virtual Screening tool WEGA v2015. A pharmacophore model based in the structure of varenicline was created by means of LigandScout v4.08. The in-silico screening was performed using Relative Pharmacophore Fit (RPF) scoring function implemented in LigandScout. Up to 3 mismatches with varenicline pharmacophore model were allowed for hits retrieving.\n\nResultsDrugbank database was screened in silico to find alternative molecules to varenicline, and the compound cevimeline was found to have strong similarity to varenicline in terms of 3D shape and pharmacophoric features. Thus, we propose this hit may interact with nicotinic 4{beta}2-Ach receptor in the same mode as varenicline does.\n\nDiscussionThe functional activities of this compound and its validity as a drug therapy for obesity treatment must be confirmed in further in vitro, in vivo and preclinical studies; however, attending to our screening procedure, this compound should be a promising therapy for such a complex disorder such as obesity.

bioinformatics↗