Search Results (7)

The restoration of mutant p53 stability is a highly sought-after strategy in targeted cancer therapy. This study presents a structure-based virtual screening and molecular dynamics approach to nominate FDA-approved drugs as candidate stabilizers of mutant p53 for downstream experimental validation. A virtual screening library of FDA-approved compounds was docked against three representative p53 mutants (7DHY, 7DHZ, and 7V97) to evaluate their binding potential. The prioritized candidates demonstrated consistent, multi-conformer binding affinities. Protein–ligand interaction profiling revealed that the candidate DB09280 possesses a highly dense interaction network, particularly against the V272M and R249S variants. Residue-level analysis of the G245S structural mutant showed that DB09280 uniquely engages His19, a crucial residue for zinc coordination, and forms stabilizing contacts with adjacent flexible loop residues, including ASN35 and PRO32. Subsequent 500 ns molecular dynamics simulations were consistent with DB09280 acting as a putative conformational clamp on the timescale sampled. The ligand-bound (holo) system exhibited substantially reduced global structural drift (RMSD) and attenuated local residue fluctuation (RMSF) within the core domain compared to the highly unstable apo state. Principal component analysis further indicated that DB09280 restricts the broad conformational sampling of the mutant into a stable, dominant basin within the sampled trajectory. Together, these computational findings nominate DB09280 as a promising candidate structural stabilizer of mutant p53 worthy of experimental follow-up. We emphasize that the in silico stabilization observed here is not equivalent to functional rescue of p53 transcriptional activity; biochemical, biophysical, and cell-based assays will be required to establish whether DB09280 restores wild-type-like DNA binding or tumor-suppressor function in mutant p53 contexts. Full article

The progressive development of resistance in Neisseria gonorrhoeae to almost all available antibiotics has made it crucial to develop novel approaches to tackling multi-drug resistance (MDR). One of the primary causes of antibiotic resistance is the over-expression of the MtrCDE efflux pump protein, making this protein a vital target for fighting against antimicrobial resistance (AMR) in N. gonorrhoeae. This study was aimed at evaluating the potential MtrCDE efflux pump inhibitors (EPIs) and their stability in treating gonorrhoea infection. This is significant because finding novel EPIs would allow for the longer maintenance of antibiotics at therapeutic levels, thereby prolonging the susceptibility of currently available antibiotics. A virtual screening of the selected Helichrysum populifolium compounds (4,5-dicaffeoylquinic acid, apigeninin-7-glucoside, and carvacrol) was conducted to evaluate their potential EPI activity. An integrated computational framework consisting of molecular docking (MD), molecular mechanics generalized born, and surface area solvation (MMGBSA) analysis, molecular dynamics simulations (MDS), and absorption, distribution, metabolism, and excretion (ADME) properties calculations were conducted. Of the tested compounds, 4,5-dicaffeoylquinic acid revealed the highest molecular docking binding energies (−8.8 kcal/mol), equivalent MMGBSA binding free energy (−54.82 kcal/mol), indicative of consistent binding affinity with the MtrD protein, reduced deviations and flexibility (root mean square deviation (RMSD) of 5.65 Å) and, given by root mean square fluctuation (RMSF) of 1.877 Å. Carvacrol revealed a docking score of −6.0 kcal/mol and a MMGBSA computed BFE of −16.69 kcal/mol, demonstrating the lowest binding affinity to the MtrD efflux pump compared to the remaining test compounds. However, the average RMSD (4.45 Å) and RMSF (1.638 Å) of carvacrol-bound MtrD protein showed no significant difference from the unbound MtrD protein, except for the reference compounds, implying consistent MtrD conformation throughout simulations and indicates a desirable feature during drug design. Additionally, carvacrol obeyed the Lipinski rule of five which confirmed the compound’s drug-likeness properties making it the most promising EPI candidate based on its combined attributes of a reasonable binding affinity, sustained stability during MDS, its obedience to the Lipinski rule of five and compliance with drug-likeness criteria. An in vitro validation of the potential EPI activities of H. populifolium compounds confirmed that 4,5-dicaffeoylquinic acid reduced the expulsion of the bis-benzimide dye by MtrCDE pump, while carvacrol showed low accumulation compared to other compounds. While 4,5-dicaffeoylquinic acid demonstrated the highest binding affinity in computational analysis and an EPI activity in vitro, it showed lower stability compared to the other compounds, as indicated in MDS. This leaves carvacrol, as a better EPI candidate for the management of gonorrhoea infection. Full article

The African Swine Fever virus (ASFV) causes an infectious viral disease in pigs of all ages. The development of antiviral drugs primarily aimed at inhibition of proteases required for the proteolysis of viral polyproteins. In this study, the conformation of the pS273R protease in physiological states were investigated, virtually screened the multi-protein conformation of pS273R target proteins, combined various molecular docking scoring functions, and identified five potential drugs from the Food and Drug Administration drug library that may inhibit pS273R. Subsequent validation of the dynamic interactions of pS273R with the five putative inhibitors was achieved using molecular dynamics simulations and binding free energy calculations using the molecular mechanics/Poison-Boltzmann (Generalized Born) (MM/PB(GB)SA) surface area. These findings demonstrate that the arm domain and Thr159-Lys167 loop region of pS273R are significantly more flexible compared to the core structural domain, and the Thr159-Lys167 loop region can serve as a “gatekeeper” in the substrate channel. Leucovorin, Carboprost, Protirelin, Flavin Mononucleotide, and Lovastatin Acid all have Gibbs binding free energies with pS273R that were less than −20 Kcal/mol according to the MM/PBSA analyses. In contrast to pS273R in the free energy landscape, the inhibitor and drug complexes of pS273R showed distinct structural group distributions. These five drugs may be used as potential inhibitors of pS273R and may serve as future drug candidates for treating ASFV. Full article

The COVID-19 pandemic caused by SARS-CoV-2 is unprecedented in recent memory owing to the non-stop escalation in number of infections and deaths in almost every country of the world. The lack of treatment options further worsens the scenario, thereby necessitating the exploration of already existing US FDA-approved drugs for their effectiveness against COVID-19. In the present study, we have performed virtual screening of nutraceuticals available from DrugBank against 14 SARS-CoV-2 proteins. Molecular docking identified several inhibitors, two of which, rutin and NADH, displayed strong binding affinities and inhibitory potential against SARS-CoV-2 proteins. Further normal model-based simulations were performed to gain insights into the conformational transitions in proteins induced by the drugs. The computational analysis in the present study paves the way for experimental validation and development of multi-target guided inhibitors to fight COVID-19. Full article

With tuberculosis still being one of leading causes of death in the world and the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), researchers have been seeking to find further therapeutic strategies or more specific molecular targets. PknB is one of the 11 Ser/Thr protein kinases of Mtb and is responsible for phosphorylation-mediated signaling, mainly involved in cell wall synthesis, cell division and metabolism. With the amount of structural information available and the great interest in protein kinases, PknB has become an attractive target for drug development. This work describes the optimization and application of an in silico computational protocol to find new PknB inhibitors. This multi-level computational approach combines protein–ligand docking, structure-based virtual screening, molecular dynamics simulations and free energy calculations. The optimized protocol was applied to screen a large dataset containing 129,650 molecules, obtained from the ZINC/FDA-Approved database, Mu.Ta.Lig Virtual Chemotheca and Chimiothèque Nationale. It was observed that the most promising compounds selected occupy the adenine-binding pocket in PknB, and the main interacting residues are Leu17, Val26, Tyr94 and Met155. Only one of the compounds was able to move the active site residues into an open conformation. It was also observed that the P-loop and magnesium position loops change according to the characteristics of the ligand. This protocol led to the identification of six compounds for further experimental testing while also providing additional structural information for the design of more specific and more effective derivatives. Full article

Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium that is present commonly in soil and water and is responsible for causing septic shock, pneumonia, urinary tract and gastrointestinal infections, etc. The multi-drug resistance (MDR) phenomenon has increased dramatically in past years and is now considered a major threat globally, so there is an urgent need to develop new strategies to overcome drug resistance by P. aeruginosa. In P. aeruginosa, a major factor of drug resistance is associated to the formation of biofilms by the LasR enzyme, which regulates quorum sensing and has been reported as a new therapeutic target for designing novel antibacterial molecules. In this study, virtual screening and molecular docking were performed against the ligand binding domain (LBD) of LasR by employing a pharmacophore hypothesis for the screening of 2373 FDA-approved compounds to filter top-scoring hit compounds. Six inhibitors out of 2373 compounds were found to have binding affinities close to that of known LasR inhibitors. The binding modes of these compounds to the binding site in LasR-LBD were analyzed to identify the key interactions that contribute to the inhibition of LasR activity. Then, 50 ns simulations of top hit compounds were performed to elucidate the stability of their binding conformations with the LasR-LBD. This study, thus concluded that sulfamerazine showed the highest binding affinity for the LasR-LBD binding pocket exhibiting strong inhibitory binding interactions during molecular dynamics (MD) simulation. Full article

DNA gyrases are enzymes that control the topology of DNA in bacteria cells. This is a vital function for bacteria. For this reason, DNA gyrases are targeted by widely used antibiotics such as quinolones. Recently, structural and biochemical investigations identified a new class of DNA gyrase inhibitors called NBTIs (i.e., novel bacterial topoisomerase inhibitors). NBTIs are particularly promising because they are active against multi-drug resistant bacteria, an alarming clinical issue. Structural data recently demonstrated that these NBTIs bind tightly to a newly identified pocket at the dimer interface of the DNA–protein complex. In the present study, we used molecular dynamics (MD) simulations and docking calculations to shed new light on the binding of NBTIs to this site. Interestingly, our MD simulations demonstrate the intrinsic flexibility of this binding site, which allows the pocket to adapt its conformation and form optimal interactions with the ligand. In particular, we examined two ligands, AM8085 and AM8191, which induced a repositioning of a key aspartate (Asp83B), whose side chain can rotate within the binding site. The conformational rearrangement of Asp83B allows the formation of a newly identified H-bond interaction with an NH on the bound NBTI, which seems important for the binding of NBTIs having such functionality. We validated these findings through docking calculations using an extended set of cognate oxabicyclooctane-linked NBTIs derivatives (~150, in total), screened against multiple target conformations. The newly identified H-bond interaction significantly improves the docking enrichment. These insights could be helpful for future virtual screening campaigns against DNA gyrase. Full article