Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16, 21, and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16, 21 and 39 significantly inhibited EGFRwt activity with IC50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors.

Antimicrobial peptide (AMP) is the polypeptide, which protects the organism avoiding attack from pathogenic bacteria. Studies have shown that there were some antimicrobial peptides with molecular action mechanism involved in crossing the cell membrane without inducing severe membrane collapse, then interacting with cytoplasmic target-nucleic acid, and exerting antibacterial activity by interfacing the transmission of genetic information of pathogenic microorganisms. However, the relationship between the antibacterial activities and peptide structures was still unclear. Therefore, in the present work, a series of AMPs with a sequence of 20 amino acids was extracted from DBAASP database, then, quantitative structure-activity relationship (QSAR) methods were conducted on these peptides. In addition, novel antimicrobial peptides with  stronger antimicrobial activities were designed according to the information originated from the constructed models. Hence, the outcome of this study would lay a solid foundation for the in-silico design and exploration of novel antibacterial peptides with improved activity activities.

1,4-dihydropyridine derivatives (1,4-DHPs) are a class of drugs used to treat cardiovascular diseases, but these drugs can cause liver injury. To reveal the toxicity characteristics of these compounds, we used a series of assays, including cell viability, enzyme activity detection, and western blotting, to investigate the toxicity of seven kinds of 1,4-DHPs (0-100 μM) on HepG2 cells and establish 3D-QSAR model based on relevant toxicity data. After HepG2 cells were treated with 1,4-DHPs for 24 h, high-dose (100 μM) 1,4-DHPs decreased cell viability to varying degrees, while ROS and MDA contents were significantly increased, and ATP content was reduced. Moreover, with the concentration of 100 μM 1,4-DHPs (Nimodipine, Nitrendipine, Cilnidipine, and Manidipine) were markedly inhibited the phosphorylation levels of mTOR protein. The results of the 3D-QSAR model showed that the non-cross validation coefficient (R2) and cross validation coefficient (Q2) of the model were 0.982 and 0.652, respectively. Combined with external validation and the Williams diagram, the model showed good predictability and application domain. Based on the CoMSIA 3D contour map, the introduction of large volume and hydrogen bond receptor groups on the carbonyl oxygen side chains of the 1,4-DHPs ring 3- and 5- was beneficial for reducing the toxicity of 1,4-DHPs. The results of this study could supplement information on the cytotoxicity of 1,4-DHPs, and could provide theoretical support for predicting the toxicity of 1,4-DHPs.

BACKGROUND: Recent studies have found that Phosphodiesterase-4 (PDE4) is closely related to the pathogenesis of depression, cognitive impairment and neurological impairment.
OBJECTIVE: Our objective is to develop potent inhibitors of the high-affinity phosphodiesterase 4D isoform (PDE4D) that can serve as radioligands for Positron Emission Tomography (PET) imaging, thereby advancing research in the field of neurological diseases.
METHODS: We employed a multi-step approach combining three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, classification techniques, and CoMSIA analysis to investigate the conformational relationship of highaffinity PDE4D inhibitors as PET ligands. ADMET and Drug-likeness predictions were also conducted. By utilizing these methods, our aim was to identify more potent PDE4D inhibitors.
RESULTS: The results showed that the CoMSIA model with the best principal component scores (n=7) had a cross-validated Q2 value of 0.602 and a non-cross-validated R2 value of 0.976. These results affirmed the excellent predictive capability of the established CoMSIA model. Analysis of the generated 3D-QSAR contour plots highlighted specific regions in the molecular structure of the compounds that can be further optimized and modified. Guided by the contour plots, we designed 100 novel PDE4D inhibitors, and molecular docking was performed for the top 4 compounds with high activity. The molecular docking scores were promising, and ADMET and drug similarity predictions yielded satisfactory results. Taking into consideration these factors, compound 51c was determined to be the optimal compound, laying a solid foundation for further research.
CONCLUSIONS: For the continued development of PDE4D PET radioligand, these models and new compounds\' developing methodology offer a theoretical foundation and crucial references.

According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds.

MMP-2 is potentially contributing to several cancer progressions including leukaemias. Therefore, considering MMP-2 as a promising target, novel anticancer compounds may be designed. Here, 32 in-house arylsulfonyl L-(+) glutamines were subjected to various structure-based computational modelling approaches to recognize crucial structural attributes along with the spatial orientation for higher MMP-2 inhibition. Again, the docking-based 2D-QSAR study revealed that the Coulomb energy conferred by Tyr142 and total interaction energy conferred by Ala84 was crucial for MMP-2 inhibition. Importantly, the docking-dependent CoMFA and CoMSIA study revealed the importance of favourable steric, electrostatic, and hydrophobic substituents at the terminal phenyl ring. The MD simulation study revealed a lower fluctuation in the RMSD, RMSF, and Rg values indicating stable binding interactions of MMP-2 and these molecules. Moreover, the residual hydrogen bond and their interaction analysis disclosed crucial amino acid residues responsible for forming potential hydrogen bonding for higher MMP-2 inhibition. The results can effectively aid in the design and discovery of promising small-molecule drug-like MMP-2 inhibitors with greater anticancer potential in the future.

Acute myeloid leukemia, a serious condition affecting stem cells, drives uncontrollable myeloblast proliferation, leading to accumulation. Extensive research seeks rapid, effective chemotherapeutics. A potential option is a BRD4 inhibitor, known for suppressing cell proliferation. Sulfonamide derivatives probed essential structural elements for potent BRD4 inhibitors. To achieve this goal, we employed 3D-QSAR molecular modeling techniques, including CoMFA, CoMSIA, and HQSAR models, along with molecular docking and molecular dynamics simulations. The validation of the 2D/3D QSAR models, both internally and externally, underscores their robustness and reliability. The contour plots derived from CoMFA, CoMSIA, and HQSAR analyses played a pivotal role in shaping the design of effective BRD4 inhibitors. Importantly, our findings highlight the advantageous impact of incorporating bulkier substituents on the pyridinone ring and hydrophobic/electrostatic substituents on the methoxy-substituted phenyl ring, enhancing interactions with the BRD4 target. The interaction mode of the new compounds with the BRD4 receptor (PDB ID: 4BJX) was investigated using molecular docking simulations, revealing favorable binding energies, supported by the formation of hydrogen and hydrophobic bonds with key protein residues. Moreover, these novel inhibitors exhibited good oral bioavailability and demonstrated non-toxic properties based on ADMET analysis. Furthermore, the newly designed compounds along with the most active one from series 58, underwent a molecular dynamics simulation to analyze their behavior. The simulation provided additional evidence to support the molecular docking results, confirming the sustained stability of the analyzed molecules over the trajectory. This outcome could serve as a valuable reference for designing and developing novel and effective BRD4 inhibitors.Communicated by Ramaswamy H. Sarma.

2,4-Disubstituted quinoline derivatives were designed based on a 3D-QSAR study, synthesized and evaluated for antimalarial activity. A large dataset of 178 quinoline derivatives was used to perform a 3D-QSAR study using CoMFA and CoMSIA models. PLS analysis provided statistically validated results for CoMFA (r2ncv = 0.969, q2 = 0.677, r2cv = 0.682) and CoMSIA (r2ncv = 0.962, q2 = 0.741, r2cv = 0.683) models. Two series of a total of 40 2,4-disubstituted quinoline derivatives were designed with amide (quinoline-4-carboxamide) and secondary amine (4-aminoquinoline) linkers at the -C4 position of the quinoline ring. For the purpose of selecting better compounds for synthesis with good pEC50 values, activity prediction was carried out using CoMFA and CoMSIA models. Finally, a total of 10 2,4-disubstituted quinoline derivatives were synthesized, and screened for their antimalarial activity based on the reduction of parasitaemia. Compound #5 with amide linker and compound #19 with secondary amine linkers at the -C4 position of the quinoline ring showed maximum reductions of 64% and 57%, respectively, in the level of parasitaemia. In vivo screening assay confirmed and validated the findings of the 3D-QSAR study for the design of quinoline derivatives.

BACKGROUND: 1, 8-naphthimide is a novel tumor inhibitor targeting nuclear DNA, which makes it applicable to the design and development of anti-osteosarcoma drugs.
OBJECTIVE: The aim of this study is to establish a satisfactory model based on 1, 8-naphthimide derivatives that makes reliable prediction as DNA-targeted chemotherapy agents for osteosarcoma.
METHODS: All compounds are constructed using ChemDraw software and subsequently optimized using Sybyl software. COMSIA method is used to construct QSAR model with the optimized compound in Sybyl software package. A series of new 1, 8-naphthalimide derivatives are designed and their IC50 values are predicted using the QSAR model. Finally, the newly designed compounds are screened according to IC50 values, and molecular docking experiments are conducted on the top ten compounds of IC50.
RESULTS: The COMSIA model shows that q2 is 0.529 and the optimum number of components is 6. The model has a high r2 value of 0.993 and a low SEE of 0.033, with the F value and the r2 predicted to be 495.841 and 0.996 respectively. The statistical results and verification results of the model are satisfactory. In addition, analyzing the contour maps is conducive to finding the structural requirements.
CONCLUSIONS: The results of this study can provide guidance for medical chemists and other related workers to develop targeted chemotherapy drugs for osteosarcoma.

Increasing evidence has shown collagen hydrolysate involves a variety of bioactivities. In our previous study, multiple antiplatelet peptides containing Hyp/Pro-Gly were identified in collagen hydrolysates from Salmo salar and silver carp skin and exhibited anti-thrombosis activity without bleeding risks in vivo. However, the relationship between structure and activity remains unknown. We performed 3D-QSAR studies on 23 Hyp/Pro-Gly-containing peptides in which 13 peptides were reported before. CoMFA, Topomer CoMFA and CoMSIA analyses were used to generate the QSAR models. Topomer CoMFA analysis showed a q2 value of 0.710, an r2 value of 0.826, an r2pred value of 0.930, and the results showed that Hyp instead of Pro was more important for improving the antiplatelet activity. CoMSIA analysis showed a q2 value of 0.461, an r2 value of 0.999, and an r2pred value of 0.999. Compared with the electrostatic field and hydrogen bond donor field, the steric field, hydrophobic field and hydrogen bond receptor field have great influence on the activity of antiplatelet peptides. The predicted peptide EOGE exhibited antiplatelet activity induced by ADP, and inhibited thrombus formation (300 μmol/kg bw) without bleeding risks. Combined results of these studies indicate that OG-containing peptides had a potential to be developed into an effective specific medical food in the prevention of thrombotic diseases.