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Phosphoinositide-3-kinases (PI3 K) are pivotal regulators of cell signaling implicated in various cancers. Particularly, mutations in the PIK3CA gene encoding the p110α catalytic subunit drive oncogenic signaling, making it an attractive therapeutic target. Our study conducted in silico exploration of 31 PIK3CA mutations across breast, endometrial, colon, and ovarian cancers, assessing their impacts on response to PI3Kα inhibitors and identifying potential non-toxic inhibitors and also elucidating their effects on protein stability and flexibility. Specifically, we observed significant alterations in the stability and flexibility of the PI3 K protein induced by these mutations. Through molecular docking analysis, we evaluated the binding interactions between the selected inhibitors and the PI3 K protein. The filtration of ligands involved calculating chemical descriptors, incorporating Veber and Lipinski rules, as well as IC50 values and toxicity predictions. This process reduced the initial dataset of 1394 ligands to 12 potential non-toxic inhibitors, and four reference inhibitors with significant biological activity in clinical trials were then chosen based on their physico-chemical properties. This analysis revealed Lig5's exceptional performance, exhibiting superior affinity and specificity compared to established reference inhibitors such as pictilisib. Lig5 formed robust binding interactions with the PI3 K protein, suggesting its potential as a highly effective therapeutic agent against PI3 K-driven cancers. Furthermore, molecular dynamics simulations provided valuable insights into Lig5's stability and its interactions with PI3 K over 100 ns. These simulations supported Lig5's potential as a versatile inhibitor capable of effectively targeting various mutational profiles of PI3 K, thereby mitigating issues related to resistance and toxicity commonly associated with current inhibitors., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Tuberculosis (TB) remains a global health challenge with the emergence of drug-resistant Mycobacterium tuberculosis variants, necessitating innovative drug molecules. One potential target is the cell wall synthesis enzyme decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), crucial for virulence and survival. This study employed virtual screening of 111 Protein Data Bank (PDB) database molecules known for their inhibitory biological activity against DprE1 with known IC50 values. Six compounds, PubChem ID: 390820, 86287492, 155294899, 155522922, 162651615, and 162665075, exhibited promising attributes as drug candidates and validated against clinical trial inhibitors BTZ043, TBA-7371, PBTZ169, and OPC-167832. Concurrently, this research focused on DprE1 mutation effects using molecular dynamic simulations. Among the 10 mutations tested, C387N significantly influenced protein behavior, leading to structural alterations observed through root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA) analysis. Ligand 2 (ID: 390820) emerged as a promising candidate through ligand-based pharmacophore analysis, displaying enhanced binding compared with reference inhibitors. Molecular dynamic simulations highlighted ligand 2's interaction with the C387N mutation, reducing fluctuations, augmenting hydrogen bonding, and influencing solvent accessibility. These collective findings emphasize ligand 2's efficacy, particularly against severe mutations, in enhancing protein-ligand complex stability. Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2's potential for advanced drug development strategies., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Pseudomonas aeruginosa is a major cause of nosocomial infections and is often associated with biofilm-mediated antibiotic resistance. The LasR protein is a key component of the quorum system in P. aeruginosa , allowing it to regulate its biofilm-induced pathogenicity. When the bacterial population reaches a sufficient density, the accumulation of N-(3-oxododecanoyl) acyl homoserine lactone (3O-C12-HSL) leads to the activation of the LasR receptor, which then acts as a transcriptional activator of target genes involved in biofilm formation and virulence, thereby increasing the bacteria's antibiotic resistance and enhancing its virulence. In this study, we performed a structure-based virtual screening of a natural food database of 10 997 compounds against the crystal structure of the ligand-binding domain of the LasR receptor (PDB ID: 3IX4). This allowed us to identify four molecules, namely ZINC000001580795, ZINC000014819517, ZINC000014708292, and ZINC000004098719, that exhibited a favorable binding mode and docking scores greater than -13 kcal/mol. Furthermore, the molecular dynamics simulation showed that these four molecules formed stable complexes with LasR during the 150-ns molecular dynamics (MD) simulation, indicating their potential for use as inhibitors of the LasR receptor in P. aeruginosa . However, further experimental validation is needed to confirm their activity., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

The increasing commercialization of new gene panels based on next-generation sequencing for clinical research has significantly improved our understanding of breast cancer genetics and has led to the discovery of new mutation variants. The study included 16 unselected Moroccan breast cancer patients tested with multi-gene panel (HEVA screen panel) using Illumina Miseq, followed by Sanger sequencing to validate the most relevant mutation. Mutational analysis revealed the presence of 13 mutations (11 single-nucleotide polymorphisms [SNPs] and 2 indels), and 6 of 11 identified SNPs were predicted as pathogenic. One of the 6 pathogenic mutations was c.7874G>C, a heterozygous SNP in HD-OB domain of BRCA2 gene, which led to the arginine to threonine change at codon 2625 of the protein. This work describes the first case of a patient with breast cancer harboring this pathogenic variant and analyzes its functional impact using molecular docking and molecular dynamics simulation. Further experimental investigations are needed to validate its pathogenicity and to verify its association with breast cancer., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Dihydrofolate reductase (DHFR) is a crucial enzyme that catalyzes the conversion of folic acid. Its reserved properties and significance in both human (h-DHFR) and mycobacterium (mt-DHFR) make it a challenging target for developing drugs against cancer and bacterial infections. Although methotrexate (MTX) is commonly used for cancer therapy and bacterial infections, it has a toxic profile. In this study, we aimed to identify selective and non-toxic inhibitors against h-DHFR and mt-DHFR using an in silico approach. From a data set of 8 412 inhibitors, 11 compounds passed the toxicity and drug-likeness tests, and their interaction with h-DHFR and mt-DHFR was studied by performing molecular docking. To evaluate the inhibitory activity of the compounds against mt-DHFR, five known reference ligands and the natural ligand (dihydrofolate) were used to generate a pharmacophoric map. Two potential selective inhibitors for mt-DHFR and h-DHFR were selected for further investigation using molecular dynamics for 100 ns. As a result, BDBM18226 was identified as the best compound selective for mt-DHFR, non-toxic, with five features listed in the map, with a binding energy of -9.6 kcal/mol. BDBM50145798 was identified as a non-toxic selective compound with a better affinity than MTX for h-DHFR. Molecular dynamics of the two best ligands suggest that they provide more stable, compact, and hydrogen bond interactions with the protein. Our findings could significantly expand the chemical space for new mt-DHFR inhibitors and provide a non-toxic alternative toward h-DHFR for the respective treatment of tuberculosis and cancer therapy., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

The rapid and global spread of the novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has raised serious public health concerns, including in Mauritania. We sequenced and analyzed the entire genome of 13 SARS-CoV-2 virus strains isolated from polymerase chain reaction (PCR)-positive symptomatic patients sampled from March 3 to May 31, 2021 to better understand SARS-CoV-2 introduction, propagation, and evolution in Mauritania. A phylogenetic tree using available data from the EpiCoV GISAID database and a variant network with non-Mauritanian sequences were constructed. Variant analysis of the 13 Mauritanian SARS-CoV-2 genome sequences indicated an average mutational percentage of 0.39, which is similar to that in other countries. Phylogenetic analysis revealed multiple spatiotemporal introductions, mainly from Europe (France, Belgium) and Africa (Senegal, Côte d'Ivoire), which also provided evidence of early community transmission. A total of 2 unique mutations, namely, NSP6_Q208K and NSP15_S273T, were detected in the NSP6 and NSP15 genes, respectively, confirming the aforementioned introduction of SARS-CoV-2 in Mauritania. These findings highlight the relevance of continuous genomic monitoring strategies for understanding virus transmission dynamics and acquiring knowledge to address forthcoming sources of infection in Africa., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

The global burden of infections and the rapid spread of viral diseases show the need for new approaches in the prevention and development of effective therapies. To this end, we aimed to explore novel inhibitor compounds that can stop replication or decrease the viral load of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which there is currently no approved treatment. Besides using the angiotensin-converting enzyme (ACE2) receptor as a main gate, the CoV-2 can bind to the glucose-regulating protein 78 (GRP78) receptor to get into the cells to start an infection. Here, we report potential inhibitors comprising small molecules and peptides that could interfere with the interaction of SARS-CoV-2 and its target cells by blocking the recognition of the GRP78 cellular receptor by the viral Spike protein. These inhibitors were discovered through an approach of in silico screening of available databases of bioactive peptides and polyphenolic compounds and the analysis of their docking modes. This process led to the selection of 9 compounds with optimal binding affinities to the target sites. The peptides (satpdb18674, satpdb18446, satpdb12488, satpdb14438, and satpdb28899) act on regions III and IV of the viral Spike protein and on its binding sites in GRP78. However, 4 polyphenols such as epigallocatechin gallate (EGCG), homoeriodictyol, isorhamnetin, and curcumin interact, in addition to the Spike protein and its binding sites in GRP78, with the ATPase domain of GRP78. Our work demonstrates that there are at least 2 approaches to block the spread of SARS-CoV-2 by preventing its fusion with the host cells via GRP78., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)