Journal of Computer-Aided Molecular Design最新文献

The accurate prediction of Drug-Target Interactions (DTIs) and Drug-Target Affinity (DTA) is crucial for reducing experimental costs and time, thereby accelerating drug discovery and repurposing efforts. The local biochemical contexts and the global structural dependencies between drugs and their target proteins are often insufficiently captured by conventional deep learning models, which restrict their predictive performance. In this work, we introduce a CNN based Dual Attention (nCNN-DA), which combines 1D convolutional feature extraction with channel and spatial attention mechanisms to enhance the representational power of features for drug SMILES and protein sequences. The model was trained and tested on three benchmark datasets: KIBA, Davis, and BindingDB, using AUPR, AUROC, MSE, Pearson correlation, and accuracy. Experimental results show that nCNN-DA significantly improves performance compared to well-established models (FusionNet, GraphormerDTI, DeepDTAGen, and DTBA-net). In particular, nCNN-DA achieved the best accuracy of 98.5%, 95.5%, and 97.5%, as well as the lowest MSE of 0.1559, 0.3189, and 0.2957 on KIBA, Davis, and BindingDB, respectively, and better scores for AUPR and Pearson Correlation. These findings further demonstrate that nCNN-DA issued for identifying putative DTI pairs and predicting binding affinities with high quality, making it a versatile and general method for drug discovery, virtual screening, and drug repurposing.

This work describes the synthesis of two novel octahedral mixed ligand transition metal complexes, FeHLAB and CuHLAB, which incorporate a combination of a Schiff-base (HL) ligand and albendazole (AB). Both of these complexes were synthesized in high yields of 88% and 85% for FeHLAB and CuHLAB, respectively, and both are thermally stable solids with a melting point of > 300 °C. Various characterization tools such as CHN & metal analysis, FT-IR, UV-Vis, magnetic susceptibility, mass spectra, molar conductance, and DFT analysis reveal an octahedral geometry involving N & O-donors along with chloride ions. The DFT results reveal that CuHLAB and FeHLAB have small HOMO-LUMO energy gaps (CuHLAB: 1.28 eV; FeHLAB: 2.96 eV) with enhanced softness and electrophilicity. All these make these complexes more chemically reactive. Antimicrobial activity was conducted, showing that metal complexes had high activity against four bacteria (E. coli, P. aeruginosa, B. cereus, S. aureus) and two fungi (A. flavus, C. albicans). CuHLAB was more active compared to FeHLAB and approached the activity of commercial medicines, which was in the range of 40-50 µM for the CuHLAB complex. A molecular docking study with E. coli DNA gyrase B (PDB code: 4DUH) showed that there was a binding affinity of - 8.80 kcal/mol for CuHLAB, which was mediated by hydrogen bonding, electrostatic, and hydrophobic interactions. This was consistent with its observed in vitro antimicrobial properties. In general, these mixed transition metal complexes, particularly CuHLAB, show strong antimicrobial activity, which provides an important approach to conserving water, soil, and public health as well as potentially thwarting economic loss.

The Euphorbiaceae family Euphorbia pulcherrima is well known for its anticancer properties. The research examines the roles of two flavonoids found in E. pulcherrima in the inhibition of thymidine phosphorylase (TP), an enzyme in cancer development, metastasis, and chemotherapy resistance. This study was designed to evaluate the in vitro TP inhibitory activity of two flavonoids isolated from E. pulcherrima and to investigate their potential binding modes and interactions with TP using molecular docking analysis. In the current studies, the chemical constituents of E. pulcherrima were isolated and characterized. Both of the constituents were flavonoids, namely-5,7,8,3',4'-pentahydroxy-3-methoxyflavone (Flavonoid 1) and kaempferol-3-β-D-glucopyranosyl (Flavonoid 2). Both of the flavonoids were evaluated spectrophotometrically for TP inhibitory activity as compared to the 7-deazaxanthine, and the IC₅₀ values were determined. Molecular docking was performed to explore the protein-ligand interactions at the TP active site. Both the flavonoids significantly antagonized TP. The maximum inhibitory effect of flavonoid 1 was 83.60% at 0.2 µM and an IC₅₀ of 12.60 ± 1.00µM. At a concentration of 0.2 µM, flavonoid 2 showed 78.09% TP inhibition, with an IC₅₀ of 19.09 ± 1.40 µM. These findings were supported by docking results according to which Flavonoid 1 had a better predicted binding affinity (-8.5 kcal/mol) than Flavonoid 2 (-4.8 kcal/mol). Moreover, Flavonoid 1 was predicted to exhibit better drug-like properties and increased bioavailability compared to Flavonoid 2, whose sizeable sugar group reduced the compound's predicted bioavailability. The results indicate Flavonoid 1 is a promising anti-cancer lead compound, as it has a strong TP inhibition, good pharmacokinetic profiles, and low toxicity. Further preclinical testing of Flavonoid 1 should be done.

Cardiovascular diseases remain the leading global cause of mortality, largely due to the limited regenerative capacity of adult cardiac tissue. Thyroid hormones, particularly tri-iodothyronine (T3), have been shown to stimulate cardiomyocyte proliferation through activation of the thyroid hormone receptor alpha (TRα), making this receptor a promising therapeutic target. Here we report a hierarchical and consensus, multi-level virtual screening pipeline integrating Molecular Mechanics (MM), Quantum Mechanics (QM), hybrid QM/MM calculations, and reactivity analysis based on the Fukui function to identify novel TRα agonists. Starting from 412 million compounds in the ZINC15 database, physicochemical filtering, validated pharmacophore matching, and docking guided by ROC curve optimization yielded 568 candidates, from which eight compounds were selected through chemically guided visual inspection. Binding affinity was evaluated with MD/MM-PBSA, PM7, and QM/MM (B3LYP/6-31G*/CHARMM36), and complemented by Fukui reactivity mapping to rationalize protein-ligand recognition. Two ligands, including the approved drug Cetraxate, consistently showed favorable interaction energies and reactivity patterns comparable to T3, suggesting agonistic potential. This work provides a rigorous, multi-scale computational framework and identifies two mechanistically supported TRα agonist candidates for future experimental validation in cardiac regeneration.

Inhibition of carbohydrate digesting enzymes like pancreatic α-amylase has proven to be an effective strategy in countering postprandial hyperglycaemia. However, unwanted adverse effects associated with current therapies, such as ACB, voglibose, and miglitol, have necessitated the development of safer and more effective alternatives. These challenges have prompted growing interest in natural product scaffolds, particularly phenolic compounds, which exhibit favourable safety profiles and multifaceted enzyme inhibition. In this context, the strategic design of molecular conjugates integrating bioactive phenolics offers a promising route to enhance inhibitory potency, binding specificity, and therapeutic relevance. Reportedly, molecular hybrids with chalcone, phenolic acid, coumarin and polyphenol backbone exhibited impressive antioxidant and potent inhibition against digestive enzymes. In the quest of developing novel anti-hyperglycaemic agents, we report in vitro and in silico evaluation of the novel TPAC as potential pancreatic α-amylase inhibitors in the present work. Among the ten conjugates, T5 (IC₅₀ = 50.65 ± 0.76 µM) exhibited strong inhibition against PPA which was comparable to positive control ACB (24.81 ± 0.98 µM). Computational binding analysis revealed binding of T5 to HPA (PDB ID: 2QV4) by interacting with the amino acid residues and distorting the receptor's catalytic site conformation. Furthermore, the conformational dynamic studies and electron density driven simulations established the stability and high reactivity of T5 within the ligand-receptor complex. The in silico studies corroborated the in vitro enzyme inhibition results, reinforcing the mechanistic insights into ligand-receptor interactions. Taken together, the experimental and computational results indicate that T5 merits further investigation as a candidate molecule targeting pancreatic α-amylase for the management of T2D .