Current Computer - Aided Drug Design - Volume 21, Issue 2, 2025

Inflammatory bowel disease (IBD) has become one of the public problems worldwide and its incidence rate is increasing year by year. Its concomitant disease i.e. diabetes mellitus (DM) has attracted more and more attention due to DM altering the progression of IBD and leading to long periods of intermittent recurrence and deterioration. The common mechanism and potential target drug of IBD with comorbid chronic conditions of DM were explored.

Gene expression profile data were downloaded from the Gene Expression Omnibus (GEO) public database. The differentially expressed genes (DEGs) were identified by R software. GO annotation and pathway enrichment were performed, a protein-protein interaction (PPI) network was constructed, associated lncRNAs were predicted and drug prediction targeting key genes was made. Additionally, the regulatory network among core genes, associated pathways, and predicted lncRNA in IBD with coexistent DM were visualized.

We identified the critical gene MMP3 with lncRNA CDKN2BAS involved in the PPAR pathway, which uncovered the underlying regulatory mechanism of IBD with coexistent DM. We also predicted the potential therapeutic compound ZINC05905909 acting on MMP3.

Our findings revealed the regulatory mechanism chain of critical gene MMP3, lncRNA CDKN2BAS, and PPAR pathway and provided potential therapeutic compound ZINC05905909 for drug therapy to treat comorbid IBD DM.

Klebsiella species have emerged as well-known opportunistic pathogens causing nosocomial infections with β-lactamase-mediated resistance as a prevalent antibiotic resistance mechanism. The discovery and emergence of metallo-β-lactamases, mainly new-Delhi metallo-β-lactamases (NDMs), have increased the threat and challenges in healthcare facilities.

A computational screening was conducted using 570 natural compounds from Dr. Duke’s Phytochemical and Ethnobotanical data to discover promising inhibitors for NDM-6, NDM-9, and NDM-23 of the Klebsiella species.

Using homology modeling on the Raptor-X web server, the structures of the three NDM variants were predicted. The structures were validated using various computational tools and MD simulation for 50 ns. Lipinski - Vebers’ Filter and ADMET Screening were used to screen 570 compounds, followed by docking in Biovia Discovery Studio 2019 using the CDOCKER module. GROMACS was used to simulate the compounds with the highest scores with the proteins for 50 ns. Using the MM-PBSA method and g_mmpbsa tool, binding free energies were estimated and per-residue decomposition analysis was conducted.

The three structures predicted were found stable after the 50 ns MD Simulation run. The compounds Budmunchiamine-A and Rhamnocitrin were found to have the best binding energy towards NDM-6, NDM-9, and NDM-23, respectively. From the results of MD Simulation, MM-PBSA binding free energy calculations, and per-residue decomposition analysis, the Protein-ligand complex of NDM-6 with Budmunchiamine A and NDM-9 with Rhamnocitrin was relatively more stable than the complex of NDM-23 and Rhamnocitrin.

The study suggests that Budmunchiamine-A and Rhamnocitrin are potential inhibitors of NDM-6 and NDM-9, respectively, and may pave a path for in-vivo and in-vitro studies in the future.

Sepsis-related acute respiratory distress syndrome (ARDS) is a fatal disease without effective therapy. Kaempferol is a flavonoid compound extracted from natural plant products; it exerts numerous pharmacological effects. Kaempferol attenuates sepsis-related ARDS; however, the underlying protective mechanism has not been elucidated completely.

This study aimed to use network pharmacology and experimental verification to investigate the mechanisms by which kaempferol attenuates sepsis-related ARDS.

We screened the targets of kaempferol by PharMapper, Swiss Target Prediction, and CTD database. We identified the targets of sepsis-related ARDS by GeneCards, DisGeNet, OMIM, and TTD. The Weishengxin platform was used to map the targets of both kaempferol and sepsis-related ARDS. We created a Venn diagram to identify the intersection targets. We constructed the “component-intersection targets-disease” network diagram using Cytoscape 3.9.1 software. The intersection targets were imported into the STRING database for developing the protein-protein interaction network. Metascape was used for the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We selected the leading 20 KEGG pathways to establish the KEGG relationship network. Finally, we performed experimental verification to confirm our prediction results.

Through database screening, we obtained 502, 360, and 78 kaempferol targets, disease targets of sepsis-related ARDS, and intersection targets, respectively. The core targets consisted of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, albumin (ALB), IL-1β, and AKT serine/threonine kinase (AKT)1. GO enrichment analysis identified 426 items, which were principally involved in response to lipopolysaccharide, regulation of inflammatory response, inflammatory response, positive regulation of cell migration, positive regulation of cell adhesion, positive regulation of protein phosphorylation, response to hormone, regulation of reactive oxygen species (ROS) metabolic process, negative regulation of apoptotic signaling pathway, and response to decreased oxygen levels. KEGG enrichment analysis identified 151 pathways. After eliminating the disease and generalized pathways, we obtained the hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and phosphoinositide 3-kinase (PI3K)-Akt signaling pathways. Our experimental verification confirmed that kaempferol blocked the HIF-1, NF-κB, and PI3K-Akt signaling pathways, diminished TNF-α, IL-1β, and IL-6 expressions, suppressed ROS production, and inhibited apoptosis in lipopolysaccharide (LPS)-induced murine alveolar macrophage (MH-S) cells.

Kaempferol can reduce inflammatory response, ROS production, and cell apoptosis by acting on the HIF-1, NF-κB, and PI3K-Akt signaling pathways, thereby alleviating sepsis-related ARDS.

It has been reported that the extension of conjugation in chalcone scaffolds considerably enhanced the potency, selectivity, reversibility, and competitive mode of MAO-B inhibition. In this study, using the experimental results of IC50 values of fifteen halogenated conjugated dienone derivatives (MK1-MK15) against MAO-B, we developed a 3D-QSAR model.

Further, we created a 3D pharmacophore model in active compounds in the series. The built model selected three variables (G2U, RDF115m, RDF155m) among the 653 AlvaDesc molecular descriptors, with a r² value of 0.87 and a Q²cv for cross-validation equal to 0.82. The three variables were mostly associated with the direction of symmetry and the likelihood of discovering massive atoms at great distances. The evaluated molecules exhibited a good correlation between experimental and predicted data, indicating that the IC50 value of the structure MK2 was related to the interatomic distances of 15.5 Å between bromine and chloro substituents. Furthermore, the molecules in the series with the highest activity were those with enhanced second component symmetry directional index from the 3D representation, which included the structures MK5 and MK6.

Additionally, a pharmacophore hypothesis was developed and validated using the decoy Schrodinger dataset, with an ROC score of 0.87 and an HHRR 1 fitness score that ranged from 2.783 to 3.00. The MK series exhibited a significant blood-brain barrier (BBB) permeability, according to exploratory analyses and in silico projections, and almost all analogues were expected to have strong BBB permeability.

Further DFT research revealed that electrostatics were important in the interactions with MAO-B.

Arthritis is the cause of morbidity associated with Chikungunya virus (CHIKV) infection. It persists even after the virus has been cleared from the body. MBZM-N-IBT was earlier shown to inhibit (CHIKV) infection in vitro and in vivo.

The objective of this study is to determine the ability of MBZM-N-IBT to manage arthritis independent of CHIKV infection.

The acute toxicity of MBZM-N-IBT was determined to find a permissible oral dose. Effects against inflammation and arthritis were determined in relevant preclinical models. Network pharmacology was used to propose possible modes of action.

It showed no acute toxicity orally, with an estimated LD50 of more than 5000 mg/kg in rats. It significantly reduced inflammation. Its effect against Complete Freund's Adjuvant (CFA) induced arthritis was comparable to that of Diclofenac sodium. Network pharmacology analysis revealed that MBZM-N-IBT can potentially interfere with multiple targets and pathways. MMP12 and CTSD were found to be the most probable hub targets of MBZM-N-IBT for its effect against arthritis.

In conclusion, MBZM-N-IBT is safe at 50 mg/kg and can manage arthritis independent of CHIKV infection through modulation of multiple pathways and arthritis-associated targets.

The prevalence of breast cancer presents a substantial global health concern, underscoring the ongoing need for the development of inventive therapeutic remedies.

In this investigation, an array of novel indazole-pyridine hybrids (5a-h) have been designed and synthesized to assess their potential as candidates for treating breast cancer. Subsequently, we have conducted biological evaluations to determine their cytotoxic effects on the human MCF-7 breast cancer cell line. Furthermore, in silico analysis was conducted to estimate the inhibition potential of the compounds against TrkA (Tropomyosin receptor kinase A), a specific molecular target associated with breast cancer, through molecular docking. In silico physicochemical and pharmacokinetic predictions were made to assess the compounds’ drug-like properties.

Compound 5a emerged as the most active compound among the others with GI50 < 10 μg/ml. Besides, compound 5a showed high binding energy (BE -10.7 kcal/mol) against TrkA and was stabilized within the TrkA binding pocket through hydrophobic, H-bonding, and van der Waals interactions. In silico physicochemical and pharmacokinetic prediction studies indicated that compound 5a obeyed both Lipinski’s and Veber’s rule and displayed a versatile pharmacokinetic profile, implying compound 5a to appear as a viable candidate and that it could be further refined to develop therapeutic agents for potentially treating breast cancer.

This study offers a promising direction for the advancement of innovative breast cancer treatments, highlighting the effectiveness of indazole-pyridine hybrids as potential anti-cancer agents. Further optimization and preclinical development are necessary to advance these compounds to clinical trials.

Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities.

To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA.

The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties.

Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol^-1) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability.

Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.