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In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions such as high temperatures, high shear mixing, or homogenization; maintaining a water-free and oxygen-free environment was also critical to prevent hydrolysis and oxidation. Molecular dynamics (MDs) simulations were employed to assess the stability mechanism between ACTY116 and the pLAI system. The initial structure of ACTY116 with an alpha helix conformation was constructed using SYBYL-X, and the copolymer PLGA was generated by AMBER 16; results showed that PLGA-based in situ depot gel improved conformational stability of ACTY116 through hydrogen bonds formed between peptide ACTY116 and the components of the pLAI formulation, while PLGA (Poly(DL-lactide-co-glycolide)) also created steric hindrance and shielding effects to prevent conformational changes. As a result, the chemical and conformational stability and in vivo long-acting characteristics of ACTY116 ensure its enhanced efficacy. In summary, we successfully achieved our objective of developing a highly stable peptide-loaded long-acting injectable (LAI) in situ depot gel formulation that is stable for at least 3 months under harsh conditions (40 °C, above body temperature), elucidating the underlying stabilisation mechanism, and the high stability of the ACTY116 pLAI formulation creates favourable conditions for its in vivo pharmacological activity lasting for weeks or even months. [ABSTRACT FROM AUTHOR]

The emergence of drug-resistant superbugs has necessitated a pressing need for innovative antibiotics. Antimicrobial peptides (AMPs) have demonstrated broad-spectrum antibacterial activity, reduced susceptibility to resistance, and immunomodulatory effects, rendering them promising for combating drug-resistant microorganisms. This study employed computational simulation methods to screen and design AMPs specifically targeting ESKAPE pathogens. Particularly, AMPs were rationally designed to target the BamA and obtain novel antimicrobial peptide sequences. The designed AMPs were assessed for their antibacterial activities, mechanisms, and stability. Molecular docking and dynamics simulations demonstrated the interaction of both designed AMPs, 11pep and D-11pep, with the β1, β9, β15, and β16 chains of BamA, resulting in misfolding of outer membrane proteins and antibacterial effects. Subsequent antibacterial investigations confirmed the broad-spectrum activity of both 11pep and D-11pep, with D-11pep demonstrating higher potency against resistant Gram-negative bacteria. D-11pep exhibited MICs of 16, 8, and 32 μg/mL against carbapenem-resistant Escherichia coli, carbapenem-resistant Pseudomonas aeruginosa, and multi-drug-resistant Acinetobacter baumannii, respectively, with a concomitant lower resistance induction. Mechanism of action studies confirmed that peptides could disrupt the bacterial outer membrane, aligning with the findings of molecular dynamics simulations. Additionally, D-11pep demonstrated superior stability and reduced toxicity in comparison to 11pep. The findings of this study underscore the efficacy of rational AMP design that targets BamA, along with the utilization of D-amino acid replacements as a strategy for developing AMPs against drug-resistant bacteria. [ABSTRACT FROM AUTHOR]

The transmission and infectivity of COVID-19 have caused a pandemic that has lasted for several years. This is due to the constantly changing variants and subvariants that have evolved rapidly from SARS-CoV-2. To discover drugs with therapeutic potential for COVID-19, we focused on the 3CL protease (3CLpro) of SARS-CoV-2, which has been proven to be an important target for COVID-19 infection. Computational prediction techniques are quick and accurate enough to facilitate the discovery of drugs against the 3CLpro of SARS-CoV-2. In this paper, we used both ligand-based virtual screening and structure-based virtual screening to screen the traditional Chinese medicine small molecules that have the potential to target the 3CLpro of SARS-CoV-2. MD simulations were used to confirm these results for future in vitro testing. MCCS was then used to calculate the normalized free energy of each ligand and the residue energy contribution. As a result, we found ZINC15676170, ZINC09033700, and ZINC12530139 to be the most promising antiviral therapies against the 3CLpro of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

3D-QSAR models were established using 52 compounds of pyrazolopyrimidine analogues with multiple substituents. We studied the relationship between molecular structure and inhibitory activity using comparative molecular field analysis (CoMFA), CoMFA region focusing (CoMFA-RG), and comparative molecular similarity index (CoMSIA). The results showed the model established by CoMFA-RG method was the optimal model, and its internal cross-validation correlation coefficient (q2 = 0.703) and non-cross-validation correlation coefficient (r2 = 0.981) had good statistical significance. Ten newly designed compounds were designed and their ADME/T properties were tested based on contour maps. Molecular docking method was used to analyze the interaction between compound 31 and IRAK4. At the same time, it also showed the binding mode of the new compounds to IRAK4 was the same as the compound 31; the hydrogen bond and hydrophobic bond played important roles in the binding process. Molecular dynamics simulation results showed residues Met192, Tyr262, Met265, Asp278, and Ala315 played vital roles of compounds to IRAK4. Combined DFT and free energy analysis theoretically proved compound Des07 had higher inhibitory activity than compound 31. [ABSTRACT FROM AUTHOR]

Hsp90 is a highly conserved and essential stress protein located in all eukaryotes, involved in the regulation of fungal survival, virulence and resistance, which is an important target for the treatment of fungal infections. Here, we intended to discover a novel inhibitor against Hsp90 guided by theoretical 3-dimensional quantitative structure–activity relationship (3D-QSAR) models for aminopyrazole analogs, which were constructed by the comparative molecular field analysis (CoMFA) and the comparative molecular similarity index analysis (CoMSIA) models. The CoMFA (q2 = 0.708, R2 = 0.962) and CoMSIA (q2 = 0.656, R2 = 0.922) models had good stability and predictability, and their contour maps could provide 3D visual information for structural modification. Subsequently, all the inhibitors used in modeling were docked into the binding site of Hsp90 by the Surflex-Dock method and their interaction was explored, which indicated that inhibitor complexes to Hsp90 mainly relied on hydrogen bonds, Pi–S stacking and hydrophobic interactions. Then, we designed 10 novel candidates guided by contour maps and binding modes, and their potential anti-fungal activity and ADME/T profile were predicted by 3D-QSAR models and online tools, which showed the candidates with better potency and good ADME/T properties. We achieved the stable conformation of candidates (M7 and M9) complexed to Hsp90 by molecular dynamics (MD) simulations and evaluated their binding energy and energy contribution of amino acids by MM/PBSA. Compared to reports in the literature (compound 22: −44.725), the designed candidates (M7: −51.478, M9: −54.964) had better potency represented by binding energy. Based on the energy contribution of amino acids, we identified the key residues that interacted with candidates, such as Asp82, Thr174 and Leu37, which had a crucial role in increasing the binding affinity. Thus, our study could provide theoretical clues to design an inhibitor against Hsp90 which is used as an anti-fungal agent. [ABSTRACT FROM AUTHOR]

The combination of human programmed cell death protein 1 (hPD-1) and its ligand hPD-L1 activates the immune escape of tumors, and the blockage in the PD-1/PD-L1 involved pathway can enhance the endogenous anti-tumor immunity. Therefore, blocking the interaction of PD-1 and its ligand PD-L1 has become a promising cancer immunotherapy technique. Recently, different types of small molecules and peptides have been discovered as PD-1/PD-L1 inhibitors. In the present work, in silico virtual screening and biomolecular interaction analysis (BIAcore) against our internal peptide library are used to discover peptides as probes to inhibit the binding between PD-1 and PD-L1. Particularly, RRQWFW-NH2 and RRWWRR-NH2 are found to have better docking scores of 7.69 and 8.34, respectively. Sequentially, molecular dynamics (MD) simulations and surface plasmon resonance (SPR) are used to further validate our predictions. Interestingly, our results showed that RRQWFW-NH2 and RRWWRR-NH2 show moderate activity to inhibit the protein–protein interaction between PD-1 and PD-L1, in which the experimental data are consistent with the computational data. Our research provides a robust computational method for the development of new PD-1/PD-L1 inhibitors and provides some new candidate peptide drugs for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway plays a critical role in cancer immunotherapy by reducing the immune escape. Five monoclonal antibodies that antagonized PD-1/PD-L1 interaction have been approved by the Food and Drug Administration (FDA) and marketed as immunotherapy for cancer treatment. However, some weaknesses of antibodies, such as high cost, low stability, poor amenability for oral administration, and immunogenicity, should not be overlooked. To overcome these disadvantages, small-molecule inhibitors targeting PD-L1 were developed. In the present work, we applied in silico and in vitro approaches to develop short peptides targeting PD-1 as chemical probes for the inhibition of PD-1–PD-L1 interaction. We first predicted the potential binding pocket on PD-1/PD-L1 protein–protein interface (PPI). Sequentially, we carried out virtual screening against our in-house peptide library to identify potential ligands. WANG-003, WANG-004, and WANG-005, three of our in-house peptides, were predicted to bind to PD-1 with promising docking scores. Next, we conducted molecular docking and molecular dynamics (MD) simulation for the further analysis of interactions between our peptides and PD-1. Finally, we evaluated the affinity between peptides and PD-1 by surface plasmon resonance (SPR) binding technology. The present study provides a new perspective for the development of PD-1 inhibitors that disrupt PD-1–PD-L1 interactions. These promising peptides have the potential to be utilized as a novel chemical probe for further studies, as well as providing a foundation for further designs of potent small-molecule inhibitors targeting PD-1. [ABSTRACT FROM AUTHOR]

Paracetamol is a relatively safe analgesia/antipyretic drug without the risks of addiction, dependence, tolerance, and withdrawal when used alone. However, when administrated in an opioid/paracetamol combination product, which often contains a large quantity of paracetamol, it can be potentially dangerous due to the risk of hepatotoxicity. Paracetamol is known to be metabolized into N-(4-hydroxyphenyl)-arachidonamide (AM404) via fatty acid amide hydrolase (FAAH) and into N-acetyl-p-benzoquinone imine (NAPQI) via cytochrome P450 (CYP) enzymes. However, the underlying mechanism of paracetamol is still unclear. In addition, paracetamol has the potential to interact with other drugs that are also involved with CYP family enzymes (inducer/inhibitor/substrate), an example being illicit drugs. In our present work, we looked into the relationship between paracetamol and its metabolites (AM404 and NAPQI) using molecular docking and molecular dynamics (MD) simulations. We first carried out a series of molecular docking studies between paracetamol/AM404/NAQPI and their reported targets, including CYP 2E1, FAAH, TRPA1, CB1, and TRPV1. Subsequently, we performed MD simulations and energy decomposition for CB1-AM404, TRPV1-AM404, and TRPV1-NAPQI for further investigation of the dynamics interactions. Finally, we summarized and discussed the reported drug-drug interactions between paracetamol and central nervous system drugs, especially illicit drugs. Overall, we are able to provide new insights into the structural and functional roles of paracetamol and its metabolites that can inform the potential prevention and treatment of paracetamol overdose.Paracetamol and its metabolites [ABSTRACT FROM AUTHOR]

• We used conventional 3D-QSAR methods to construct models. • Based on the already established models, we designed seven new compounds. • 3、Molecular Dynamics Simulation proved new compound D7 had good selectivity on hCA IX. • 4、The studies may be helpful in the rational drug design of isoform-selective inhibitors. Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R 2>0.75) and predictability (Q 2>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors. [ABSTRACT FROM AUTHOR]

The AdeABC efflux pump is an important mechanism causing multidrug resistance in Acinetobacter baumannii , and its main component AdeB can recognize carbapenems, aminoglycosides, and other multi-class antibiotics and efflux them intracellularly, which is an ideal target for the development of anti-multidrug resistant bacteria drugs. Here, we combined multiple computer-aided drug design methods to target AdeB to identify promising novel structural inhibitors. Virtual screening was performed by molecular docking and molecular dynamics simulation (MD) and 12 potential compounds were identified from the databases. Meanwhile, their biological activities were validated by in vitro activity assays, and ChemDiv L676–2179 (γ-IFN), ChemDiv L676–1461, and Chembridge 53717615 were confirmed to suppress efflux effects and restore antibiotic susceptibility of resistant bacteria, which are expected to be developed as adjuvant drugs for the treatment of multi-drug resistant Acinetobacter baumannii clinical infections. [ABSTRACT FROM AUTHOR]

• 52 globomycin analogs were subjected to three-dimensional quantitative conformational relationships research. • Guided by the contour maps from 3D-QSAR models, the regions and strategies for structural optimization were determined. • Combined with molecular docking, molecular dynamics simulations and binding free energy calculations to verify the predicted inhibitory activity of the analogs. • Ten new globomycin analogs with potential were obtained and provided theoretical clues for the design of highly active drugs against E. coli. Lipoprotein signal peptidase II (LspA), a promising therapeutic target for bacterial infections, is essential for the growth of Escherichia coli (E. coli). In this study, 52 globomycin analogs were subjected to three-dimensional quantitative conformational relationships (3D-QSAR) research using comparative molecular field analysis (CoMFA) and the comparative molecular similarity index analysis (CoMSIA) methods. Meanwhile, molecular mechanisms and biological activities were investigated combined with molecular docking and molecular dynamics (MD) simulation. Guided by the contour maps from 3D-QSAR models, we designed 10 novel analogs with potential antimicrobial activity against E. coli. This research could provide theoretical clues for drug design with high activity against E. coli , which was bound to the molecular target LspA. [Display omitted] [ABSTRACT FROM AUTHOR]

• GSK-3 has been proved as an important therapeutic target in type 2 diabetes mellitus and Alzheimer's disease. • The constructed 3D-QSAR model had good predictive ability. • Based on 3D-QSAR models and contour maps, we designed 10 novel compounds with good potential activity. • We explored the binding feature between GSK-3 and inhibitor by molecular docking and MD simulations. • Residues Ile62, Val70 and Lys85 located in the active site play a key role for GSK-3 complexed with inhibitors. Glycogen Synthase Kinase 3 (GSK-3) is a member of cellular kinase with various functions, such as glucose regulation, cellular differentiation, neuronal function and cell apoptosis. It has been proved as an important therapeutic target in type 2 diabetes mellitus and Alzheimer's disease. To better understand their structure–activity relationships and mechanism of action, an integrated computational study, including three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD), was performed on 79 (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine GSK-3 inhibitors. In this paper, we constructed 3D-QSAR using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) method. The results showed that the CoMFA model (q 2 = 0.743, r 2 = 0.980) and the CoMSIA model (q 2 = 0.813, r 2 = 0.976) had stable and reliable predictive ability. The electrostatic and H-bond donor fields play important roles in the models. The contour maps of the model visually showed the relationship between the activity of compounds and their three-dimensional structure. Molecular docking was used to identify the key amino acid residues at the active site of GSK-3 and explore its binding mode with ligands. Based on 3D-QSAR models, contour maps and the binding feature between GSK-3 and inhibitor, we designed 10 novel compounds with good potential activity and ADME/T profile. Molecular dynamics simulation results validated that Ile62, Val70 and Lys85 located in the active site play a key role for GSK-3 complexed with inhibitors. These results might provide important information for designing GSK-3 inhibitors with high activity. [ABSTRACT FROM AUTHOR]