Journal of Biomolecular Structure & Dynamics最新文献

Squalene synthase (SQS) plays a crucial role in the cholesterol biosynthetic pathway. Its distinctive strategic position makes it a promising candidate for targeting and developing new anti-hypercholesterolemic agents. To uncover novel phytochemical scaffolds as potential inhibitors of SQS, we employed a structure-based virtual screening approach that involves screening 545 phytochemicals collected from Moroccan aromatic and medicinal plants and filtering them based on RMSD values and their affinity towards the target enzyme. Furthermore, we visualized the interacting amino acid residues to gain insight into the 2D and 3D interactions. The docking process was validated through the re-docking method with the reference co-crystallized complex (PDB id = 3v66, SQS-D3A). The screening resulted in the identification of two phytochemicals, Apigenin 7-O-rutinoside, and Apigenin 7-O-glucuronide, with high affinity for SQS binding sites. Both phytochemicals interact with functionally essential residues of SQS. The drug-likeness and toxicity of the phytochemicals were assessed through ADME-Tox analysis. Later, molecular dynamics simulations were performed by GROMACS software for 100 ns to evaluate the stability and fluctuations of protein-ligand complexes. By examining the trajectories produced by the MD simulations, we monitored complex stability, fluctuation, atomic gyration, H-bond, PCA, and FES. The simulations demonstrated that the interaction between the target and the compounds was stable and consistent. Binding free energy calculations indicated that Apigenin 7-O-rutinoside and Apigenin 7-O-glucuronide exhibited higher binding free energy than the co-crystallized inhibitor (D3A), providing a basis for further research in vitro and in vivo to develop potent SQS inhibitors for the treatment of hypercholesterolemia.

Malaria remains a critical global health issue, particularly in tropical and subtropical regions. Understanding its biology and epidemiology is vital for developing effective prevention and control strategies. Falcipain-2 (FP-2), a cysteine protease in Plasmodium falciparum, the deadliest malaria parasite, is essential for parasite survival in red blood cells, making it an attractive drug target. Inhibiting FP-2 disrupts key metabolic processes, leading to parasite death, offering a promising antimalarial drug development avenue. This study utilized computational approaches to design novel antimalarials. We prepared large fragment libraries, Enamine (∼220,174 fragments) and ChemDiv (∼18,713 fragments), for virtual screening against FP-2 (PDB ID: 6JW9). Fragments with binding free energies ≤ -4.0 kcal/mol were selected and evolved into drug-like ligands. SP and XP docking-based screenings prioritized these ligands, refined further using MM-GBSA calculations. Promising ligands underwent 100 ns molecular dynamics simulations to assess conformational changes and complex stability. This study identified two viable inhibitors, T4 and A3, with high affinity, stability, and selectivity towards FP-2 compared to E64.Following computational studies, compound A3 and its ten analogues (KA-series) were synthesized and characterized by using multi-spectroscopic techniques with high purity confirmed by LC-MS. Biological testing against P. falciparum 3D7 strain revealed KA-5 as the most potent compound with an IC₅₀ value of 3.0 μM. Future work will involve synthesizing additional analogue series for an extensive structure-activity relationship (SAR) study. Further experimental validation is essential to develop these compounds as effective therapeutic agents for malaria treatment.

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia, posing serious health risks and becoming increasingly prevalent. Prolonged hyperglycemia can lead to complications such as nephropathy, neuropathy, retinopathy, cardiovascular damage, and blindness. Controlling hyperglycemia through α-glucosidase inhibitors, which slow down carbohydrate breakdown, is an effective treatment strategy. However, current inhibitors like acarbose, voglibose, and miglitol while used to manage type 2 diabetes, have significant side effects. Therefore, developing new α-glucosidase inhibitors that are more effective and have fewer side effects is crucial. In this study, a series of novel quinazolin-4(3H)-one-benzenesulfonamide hybrid compounds were designed, synthesized, and evaluated for in vitro α-glucosidase inhibitory activity. The compounds showed higher enzyme inhibition potency, with IC₅₀ values ranging between 129.2 ± 0.5 and 558.7 ± 13.7 µM, compared to acarbose (IC₅₀=814.3 ± 13.5 µM). Among the tested compounds, compound 10, bearing a 4-chlorophenyl ring on the nitrogen atom of the sulfonamide group, was the most active, with an IC₅₀ value of 129.2 ± 0.5 µM. Enzyme kinetics analyses and molecular modeling studies were conducted to understand their inhibition mechanisms and interactions with the enzyme. The kinetic studies revealed a mixed-type inhibition model, indicating that the compounds bind to the enzyme-substrate complex with higher affinity than to the free enzyme. Molecular modeling results confirmed these findings. Additionally, in silico prediction studies showed that the selected compounds have favourable physicochemical and drug-like properties. These results suggest these compounds have potential for further optimization and development as effective α-glucosidase inhibitors for diabetes treatment.

Dual falcipain-2 (FP-2) and falcipain-3 (FP-3) inhibitors, NM12 and NM15, displayed micromolar inhibitions but they exhibit similar binding affinities for the human cathepsins, thus indicating potential toxicity. The current study aims to develop a model to enhance the selectivity of the falcipain inhibitors vis-à-vis human cathepsins using previously identified dual falcipain 2 and 3 inhibitors, NM12 and NM15. To improve the selectivity of NM12 and NM15, analogs with weaker interactions with the conserved residues in the FPs and hCatK were designed while enhancing the unique interactions for the FPs. In silico analysis was carried out in the S2 subsite of both plasmodium and human proteases which is considered the preferred selective site due to the presence of less conserved residues. The Fasta sequence alignment and active/conserved binding site superimposition show that FPs contain acidic polar residues (Asp234 for FP2 and Glu243 for FP3) while hCatK has a neutral hydrophobic residue (Leu209) at the S2 subsite. Therefore, analogs of NM12 and NM15 were designed to enhance affinity and selectivity by improving interactions with these acidic residues while avoiding interactions with hydrophobic residues in hCatK. Newly designed analogs (NM12H and NM15G) show better selectivity as well as binding affinity towards FPs (ΔG of NM12H: -74.49 kcal/mol for FP2, -70.97 kcal/mol for FP3; ΔG of NM15G: -70.09 kcal/mol for FP2, -74.52 kcal/mol for FP3) as compared to NM12 and NM15. Thus, the selectivity and binding affinity against dual falcipains vis-à-vis human cathepsin were improved using molecular dynamic simulations.

The main protease (M^pro) stands as a pivotal enzyme crucial for coronavirus replication, thus serving as a prime target for coronavirus drug discovery endeavors. Nirmatrelvir (PF-07321332), an antiviral compound developed by Pfizer, has been engineered to selectively inhibit the M^pro of SARS-CoV-2 by directly binding to its catalytic cysteine residue (Cys145). In a bid to scrutinize the expansive inhibitory spectrum of PF-07321332 against a gamut of human pathogenic coronaviruses, we undertook an exhaustive investigation leveraging molecular dynamics (MD) simulations in conjunction with binding free energy (BFE) calculations. Molecular dockings of PF-07321332 with the M^pros of seven human coronaviruses yielded their optimal binding modes (complexes), subsequently subjected to rigorous MD simulations and BFE assessments. The results of MD simulations indicated that PF-07321332 can remain stable in the substrate-binding cavity of all the seven human coronaviruses M^pros. A detailed comparison of BFE components revealed that intermolecular van der Waals (vdW) interactions play a significantly more crucial role in maintaining association and determining the high binding affinity than intermolecular electrostatic interactions. Analyses of residue BFE decomposition reveals Cys145 as a pivotalt amino acid, positively influencing the stable binding between M^pros and inhibitor. These finding imply that PF-07321332 has the potential to be an effective anti-coronavirus inhibitor and also provide insights into inhibitor optimization and drug design strategies against human coronavirus.

Thyroid cancer (TC) is poised to become the fourth most prevalent global malignancy, highlighting the urgency for innovative therapeutic strategies. Current treatments often come with significant adverse effects, emphasizing the necessity for targeted drugs with reduced side effects. In this study, we have employed a comprehensive approach, including network pharmacology, molecular docking, molecular dynamics simulations, and MMPBSA to uncover the potential compounds within Eclipta prostrata and their interactions with SRC kinase of TC. The Src family of kinases is a versatile family of nonreceptor tyrosine kinase, regulating key cellular processes responsible for mediating thyroid tumor progression. Our aim is to harness nature's arsenal for the development of safe and effective TC therapeutics. We have identifyied six E. prostrata compounds, carefully chosen based on Lipinski's Rule of Five, bioavailability and drug-likeness scores. Additionally, our research pinpoints the top three core proteins through network pharmacology, assessing their potential for immune infiltration into cancer tissue and examining mRNA expression profiles across various pathological stages. Significantly, luteolin emerged as a primary SRC kinase inhibitor, displaying remarkable binding energy of -9.0 kcal/mol, comparable to the standard quinazoline inhibitor with binding energy of -9.5 kcal/mol. In addition, rigorous 100 nanosecond molecular dynamics simulations were performed on protein-compound complex, confirming their thermodynamic stability. Additionally, MM-PBSA also confirmed the docking results. Our in silico analysis suggested that luteolin holds promise as potent TC inhibitor, ushering in a new era in the quest for natural, low-risk therapeutic options for thyroid cancer, inspiring hope for patients and healthcare providers alike.

Uterine fibroids (UF) are reproductive conditions that occur as tumours in the womb. It is a gynecological outgrowth of diverse sizes often allied with infertility risks that might require surgery to reduce the complication in the worst-case scenario in women. Recent studies have uncovered that estrogen can induce and facilitate other target pathways' action on target cells for UF's pathogenesis, among the targets probed for pharmaceutical intervention. This study screens the interaction effects of 32 phytochemicals from indigenous and adopted potent Chinese plants and herbs; Chamomile, Pomegranate, Red clover, Cinnamomum, and Date palm, against estrogen receptor alpha (ESRα) to serve for anti-UF drug candidates using in silico tools through the molecular mechanisms. The interaction identifies coumestrol as the best-docked candidate (-9.6 kcal/mol) with a correlation to the binding free energy (-30.487 kcal/mol) as compared to the standard drug tamoxifen (-9.3 kcal/mol; -46.928 kcal/mol). The downstream post-docking evaluation reveals coumestrol to have excellent pharmacokinetics, drug-likeness, leadlikeness (no violation), less toxic (LD50; 2991 mg/kg), and highly interactive with ESRα. Coumestrol was top-ranked for ESRα (1QKU) target by PharmMapper among 300 human protein targets, with a z-score of 1.19368. The density functional theory (DFT) and dynamic simulation of 200 ns reveal regions of coumestrol structure and its complex that contribute to the chemical reactivity, stability, flexibility, and compactness of druggability. Ultimately, coumestrol emerged as a potential candidate suitable for anti-UF management, therefore future direction for its application should be on the design and synthesis of new structural derivatives for further in silico, in vitro, and in vivo studies.

The FIKK protein family, encompassing 21 serine-threonine protein kinases, is a distinctive cluster exclusive to the Apicomplexa phylum. Predominantly located in Plasmodium falciparum which is a malarial parasite, with a solitary gene identified in a distinct apicomplexan species, this family derives its nomenclature from - phenylalanine, isoleucine, lysine, lysine (FIKK), a conserved amino acid motif. Integral to the parasite's life cycle and consequential to malaria pathogenesis, the absence of orthologous proteins in eukaryotic organisms designates it as a promising antimalarial drug target. Among the FIKKs, FIKK9.5 plays a pivotal role in the parasite's development within red blood cells (RBCs). This investigation acquired the three-dimensional structure of FIKK9.5 and its ligands through extensive database searches and literature review. Computational screening of natural phytochemicals derived from plants traditionally used in antimalarial remedies was conducted by employing the Glide docking suite. AutoDock Vina was utilized to discern the inhibitor exhibiting optimal binding affinity. Subsequently, Molecular Dynamics (MD) simulations employing GROMACS validated Rufigallol as the most potent inhibitory compound against FIKK9.5. The robustness of the protein-ligand complex was scrutinized through a 200 nanosecond molecular dynamics (MD) trajectory. Trajectory analysis and determination of binding free energies were accomplished using MM-GBSA and MM-PBSA approaches. The ligand-binding exhibited sustained stability throughout the simulation, manifesting an approximate binding free energy of -25.5986 kcal/mol. This comprehensive computational study lays the groundwork for potential experimental validation in the laboratory, paving the way for the development of novel therapeutics targeting FIKK9.5 in the pursuit of innovative antimalarial.

The Nipah virus (NiV), a highly pathogenic zoonotic virus of the Paramyxoviridae family, poses significant threats with its alarming mortality rates and pandemic potential. Despite historical cases, effective therapeutics remain elusive, prompting urgent exploration of potential antivirals. In this study, a structure-based virtual screening approach was employed to evaluate 690 metabolites sourced from ten medicinal plants (Allium sativum, Andrographis paniculata, Cocos nucifera, Euphorbia hirta, Euphorbia neriifolia, Moringa oreifera, Ocimum basilicum, Piper nigrum, Vitex negundo, and Zingiber officinale) for their antiviral activity against Nipah virus proteins. Through targeted and blind docking experiments, forty-three (43) compounds were found to exhibit high binding affinities (≤ -8 Kcal mol^-1) and validated site-specificity. Subsequent analysis of the ADMET properties of these compounds, along with off-target docking to swine receptors, six (6) compounds with profiles akin to approved drugs and minimal off-target binding were identified. Stability screening via 100 ns and 300 ns molecular dynamics simulations identified two (2) of the six compounds that demonstrated sustained dynamic stability over an extended duration, coupled with favorable binding energies from MM-(GB/PB)SA calculations and biologically significant binding modes and residue interactions. Betulinic acid and CID 118716357 exhibited significant potential as inhibitors of Nipah virus fusion (F) glycoprotein trimer by targeting the oligomerization sites used to form the functional hexamer-of-trimer assembly. Coupled with their dynamic stability and favorable ADMET profiles in both human and swine conditions, these findings make them good candidates for subsequent in vitro testing and further biological screening in the quest for potent antiviral drugs targeting Nipah virus proteins.

The recent spread of SARS-CoV-2 has led to serious concerns about newly emerging infectious coronaviruses. Drug repurposing is a practical method for rapid development of antiviral agents. The viral spike protein of SARS-CoV-2 binds to its major receptor ACE2 to promote membrane fusion. Following the entry process, the spike protein is further activated by cellular proteases such as TMPRSS2 and Furin to promote viral entry into human cells. A crucial factor in preventing SARS-CoV-2 from entering target cells using HIV-1 fusion inhibitors is the similarity between the fusion mechanisms of SARS-CoV-2 and HIV-1. In this investigation, the HIV-1 fusion inhibitors CMK, Luteolin, and Naphthofluorescein were selected to understand the molecular mode of interactions and binding energy of Furin with these experimental inhibitors. The binding affinity of the three inhibitors with Furin was verified by molecular docking studies. The docking scores of CMK, Luteolin and Naphthofluorescein are -7.4 kcal/mol, -9.3 kcal/mol, and -10.7 kcal/mol, respectively. Therefore, these compounds were subjected to MD, drug-likeness, ADMET, and MM-PBSA analysis. According to the results of a 200 ns MD simulation, all tested compounds show stability with the complex and can be employed as promising inhibitors targeting SARS-CoV-2 Furin protease. In addition, pharmacokinetic analysis revealed that these compounds possess favorable drug-likeness properties. Thus, this study of Furin inhibitors helps in the evaluation of these compounds for use as novel drugs against SARS-CoV-2.