Discovery Of Inhibitors Research Articles

Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers.

One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 (6), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents (NCT04657068 and NCT05798611). ART0380 (6) has a favorable human PK profile suitable for both intermittent and continuous once-daily (QD) dosing, characterized by a dose-proportional increase in exposure and low variability.

Discovery of novel VEGFR2 inhibitors against non-small cell lung cancer based on fingerprint-enhanced graph attention convolutional network

Despite the proven inhibitory effects of drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2) on solid tumors, including non-small cell lung cancer (NSCLC), the development of anti-NSCLC drugs solely targeting VEGFR2 still faces risks such as off-target effects and limited efficacy. This study aims to develop a novel fingerprint-enhanced graph attention convolutional network (FnGATGCN) model for predicting the activity of anti-NSCLC drugs. Employing a multimodal fusion strategy, the model integrates a feature extraction layer that comprises molecular graph feature extraction and molecular fingerprint feature extraction. The performance evaluation results indicate that the model exhibits high accuracy and stability in predicting activity. Moreover, we explored the relationship between molecular features and biological activity through visualization analysis, thus improving the interpretability of the approach. Utilizing this model, we screened the ZINC database and conducted high-precision molecular docking, leading to the identification of 11 potential active molecules. Subsequently, molecular dynamics simulations and free energy calculations were performed. The results demonstrate that all 11 aforementioned molecules can stably bind to VEGFR2 under dynamic conditions. Among the short-listed compounds, the top six exhibited satisfactory inhibitory activity against VEGFR2 and A549 cells. Especially, compound Z-3 displayed VEGFR2 inhibitory with IC50 values of 0.88 μM, and anti-proliferative activity against A549 cells with IC50 values of 4.23 ± 0.45 μM. This approach combines the advantages of target-based and phenotype-based screening, facilitating the rapid and efficient identification of candidate compounds with dual activity against VEGFR2 and A549 cell lines. It provides new insights and methods for the development of anti-NSCLC drugs. Furthermore, further biological activity tests revealed that Z1-Z3 and Z6 manifested relatively strong antiproliferative activities against NCI-H23 and NCI-H460, and relatively low toxicity towards GES-1. The hit compounds were promising candidates for the further development of novel VEGFR2 inhibitors against NSCLC.

4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses.

2-(Methylthio)-N-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide 1 was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC50 = 0.6 μM; EC90 = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC50 = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure-activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of 1 led to the discovery of a new potent inhibitor N-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide 26, which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC90 of 0.45 μM with considerably improved MLM stability (t1/2 = 74 min) as compared to 1. Mechanism of action studies show that 26 inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The in vivo efficacy studies of compound 26 on CHIKV infection in mice are reported.

A Deep Dive into PDE5 Inhibition: Innovative Discoveries via Virtual Screening

Background: PDE5 inhibitors have had a surge in popularity over the last decade owing to their efficacy in the treatment of erectile dysfunction, coronary vasculopathy, and pulmonary arterial hypertension. These inhibitors exhibit competitive binding with phosphodiesterase type 5 and inhibit the hydrolysis of cyclic guanosine monophosphate, hence elevating the levels of cGMP in smooth muscle cells and prolonging the duration of an erection. However, due to production costs and side effects, further research is needed to discover new PDE5 inhibitors. Objective: The study aimed to identify potent PDE5 inhibitors by employing the extensive application of computer-aided drug design. Methods: Three different databases, named Million Molecules Database, Natural Product Database, and NCI Database, have been screened, which has been followed by filtering based on various druglikeness rules, docking, ADME, toxicity, consensus molecular docking, and 100 ns molecular dynamics simulation. Results: Three compounds (ZINC05351336, ZINC12030898, and ZINC17949426) have exhibited stable-binding characteristics at the active site of PDE5, demonstrating a robust binding affinity. These molecules have been found to possess drug-like capabilities, effective ADME features, low toxicity, and high stability. Conclusion: The study has delved into the realm of PDE5 inhibitors, which have been found to be effective in treating erectile dysfunction, but high production costs and side effects necessitate new ones. Through computer-aided drug design and screening, three compounds have been identified with promising binding characteristics, drug-appropriate properties, effective ADME profiles, minimal toxicity, and stability, making them potential candidates for future PDE5 inhibitors

Computer-assisted discovery of tyrosinase inhibitors from turmeric and clove: An in silico study on natural skin whitening agents and their potential toxicity

A computational approach was employed to identify potential tyrosinase-related protein 1 (TYRP1) inhibitors from turmeric and clove extracts, with the goal of discovering safer alternatives to the toxic hydroquinone for skin whitening applications. Gas Chromatography–Mass Spectrometry (GC–MS) analysis revealed the phytochemical composition of the plant extracts, which were then evaluated for their binding affinity to TYRP1 through molecular docking simulations. The stability of the resulting hit compounds was assessed via molecular dynamics simulations, and their dermal toxicity profiles were determined using Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis. Density Functional Theory (DFT) calculations were also performed to compare the chemical reactivity of the hit compounds to hydroquinone. The results identified 3,4-dimethoxybenzamidoxime from clove and Ar-turmerone from turmeric as potential inhibitors, exhibiting binding free energies of −6.8 kcal/mol and −6.6 kcal/mol, respectively. These values surpass those of hydroquinone (−5.1 kcal/mol) and the native ligand (−5.5 kcal/mol), suggesting potential inhibitory activity. Notably, 3,4-dimethoxybenzamidoxime exhibited favorable skin permeation properties and passed all toxicity tests, suggesting its potential as a safe and effective replacement for hydroquinone in skin whitening products.

Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain

Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-d-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A-B subsite to interact with a His61 NH proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.

A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions

A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions

Proteome-wide bioinformatic annotation and functional validation of the monotopic phosphoglycosyl transferase superfamily

Phosphoglycosyl transferases (PGTs) are membrane proteins that initiate glycoconjugate biosynthesis by transferring a phospho-sugar moiety from a soluble nucleoside diphosphate sugar to a membrane-embedded polyprenol phosphate acceptor. The centrality of PGTs in complex glycan assembly and the current lack of functional information make these enzymes high-value targets for biochemical investigation. In particular, the small monotopic PGT family is exclusively bacterial and represents the minimal functional unit of the monotopic PGT superfamily. Here, we combine a sequence similarity network analysis with a generalizable, luminescence-based activity assay to probe the substrate specificity of this family of monoPGTs in the bacterial cell-membrane fraction. This strategy allows us to identify specificity on a far more significant scale than previously achievable and correlate preferred substrate specificities with predicted structural differences within the conserved monoPGT fold. Finally, we present the proof-of-concept for a small-scale inhibitor screen (eight nucleoside analogs) with four monoPGTs of diverse substrate specificity, thus building a foundation for future inhibitor discovery initiatives.

Discovery of UCB9386: A Potent, Selective, and Brain-Penetrant Nuak1 Inhibitor Suitable for In Vivo Pharmacological Studies.

Nuak1 (NUAK family SnF1-like kinase-1) is a serine-threonine kinase and a member of the AMPK family. Interest in Nuak1 has increased over the years due to the role it plays in several biological processes, from tumor cell invasion and proliferation to Tau stabilization. Nuak1 is expressed in many cancer cell lines and many reports describe this target as an oncogene, the inhibition of which is hypothesized to be valuable for treating various cancer types including glioma. We report here the discovery of Nuak1 inhibitors originating from HTS hit 9 with excellent selectivity and the subsequent medicinal chemistry optimization program, supported by structural information from the first crystal structures of a Nuak1 chimeric protein which provided insights into the binding modes of our compounds. These efforts yielded a nanomolar cell potent, highly selective and brain penetrant Nuak1 inhibitor UCB9386 (56) suitable for in vivo pharmacological studies for central nervous system (CNS) disorders.

Computational discovery of novel GPX4 inhibitors from herbal sources as potential ferroptosis inducers in cancer therapy

Ferroptosis, a cell death regulation process dependent on iron levels, represents a promising therapeutic target in cancer treatment. However, the scarcity of potent ferroptosis inducers hinders advancement in this area. This study addresses this gap by screening the PubChem database for compounds with favorable ADMET properties to identify potential GPX4 inhibitors. A structure-based virtual screening was conducted to compare binding affinities of selected compounds to that of RSL3. The candidates—isochondrodendrine, hinokiflavone, irinotecan, and ginkgetin—were further analyzed through molecular dynamics (MD) simulations to assess their stability within the GPX4-ligand complexes. The computed binding free energies for RSL3, isochondrodendrine, hinokiflavone, irinotecan and ginkgetin were −80.12, −107.31, −132.03, and −137.52 and −91.11 kJ/mol, respectively, indicating their significantly higher inhibitory effects compared to RSL3. These findings highlight the potential for developing novel GPX4 inhibitors to promote ferroptosis, warranting further experimental validation.

Recent Studies on Heterocyclic Cholinesterase Inhibitors Against Alzheimer's Disease.

Alzheimer's disease is a progressive and neurodegenerative disease characterized by impairment in emotion, language, memory and cognitive judgment. There are many factors related to Alzheimer's disease, such as amyloid beta plaques (Aβ) due to impaired metabolism of amyloid precursor protein (APP), tau hyperphosphorylation and accumulation of neurofibrillary tangles, and disruption of the cholinergic system. Disruption of the cholinergic system responsible for cognitive function and memory processes is one of the important causes of Alzheimer's disease. Therefore, cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibitors that maintain choline (acetylcholine and butyrylcholine) levels in the synaptic gap play an important role in the symptomatic treatment of Alzheimer's disease. Numerous studies have been carried out against Alzheimer's disease involving acetylcholinesterase and butyrylcholinesterase inhibitors. However, there are very few drugs (tacrine, rivastigmine, galantamine and donepezil) approved as cholinesterase inhibitors. Therefore, cholinesterase inhibitors are needed against Alzheimer's disease. This review is focused on using heterocyclic rings that show remarkable cholinesterase inhibitory activity for Alzheimer's disease. In this review, chemical structures and structure-activity relationships of recently reported cholinesterase inhibitors are emphasized. This review will give important ideas to medicinal chemists in the discovery and development of potent cholinesterase inhibitors in their future studies.

Discovery of novel CDK2 inhibitors for cancer treatment: integrating ligand-based pharmacophore modelling, molecular docking, DFT, ADMET, and molecular dynamics simulation studies

BackgroundThe global landscape of public health faces significant challenges attributed to the prevalence of cancer and the emergence of treatment resistance. This study addresses these challenges by focusing on Cyclin-dependent Kinase 2 (CDK2) and employing a systematic computational approach for the discovery of novel cancer therapeutics.ResultsInitial ligand-based pharmacophore modelling, utilizing a training set of five reported CDK2 inhibitors, yielded a robust model characterized by Aro|Hyd| and |Acc|Don| features. Screening this validated model against the ZINC database identified 1881 hits, which were further subjected to molecular docking studies. The top 10 compounds (Z1–Z10) selected from the docking studies underwent Pharmacokinetic parameters Absorption, Distribution, Metabolism, Excretion and Toxicity profiling, Density Functional Theory (DFT) studies and the top two went for 100ns molecular dynamics (MD) simulations by comparing them with the standard Roscovitine. Compounds Z1 and Z2 emerged as the most promising, with docking scores of − 8.05 kcal/mol and − 8.02 kcal/mol, respectively. DFT analysis of the top 10 compounds revealed minimal variations in highest occupied molecular orbital–lowest unoccupied molecular orbital energy gaps, indicating consistent electronic stability and reactivity across the candidates. MD simulations of Z1 and Z2 confirmed their stable interactions with CDK2, with root mean square deviation (RMSD) values ranging from 1.4 to 2.5 Å for Z1 and 1.5 to 2.4 Å for Z2.ConclusionThe current research identified compounds Z1 and Z2, which demonstrated significant potential as potent CDK2 inhibitors for cancer therapy, providing valuable insights into the development of more effective CDK2 inhibitors and addressing the critical need for innovative therapeutic strategies in cancer treatment.Graphical abstract

Heme oxygenase 1 inhibitor discovery and formulation into nanostructured lipid carriers as potent and selective treatment against triple negative metastatic breast cancer

Heme oxygenase-1 (HO-1) has been identified as a potential new target in anticancer therapy, being overexpressed in different tumors and crucial for cell proliferation. Advances in the development of specific HO-1 inhibitors should support the understanding of controlling HO-1 activity as antitumoral strategies, opening the path for future therapeutic applications. In the present study, small series of new HO-1 inhibitors were synthesized by joining a butylimidazolic pharmacophore together with a hydrophobic moiety spaced by a 2-oxybenzamide central linker. The most active and selective HO-1 inhibitor, VP 21–04, 2-(4-(1H-imidazol-1-yl)butoxy)-N-benzyl-5-iodobenzamide (7b) was identified. This ligand showed strong cytotoxic activity against melanoma and breast cancer cell lines. Encapsulation of VP 21–04 in nanostructured lipid carriers (NLC 21–04) was performed to exploit its therapeutic potential by passive-targeting delivery ameliorating water-solubility and toxicity. Interestingly, NLC 21–04 showed a marked antiproliferative effect in both cancer cell lines, and an improved safety profile with a wider therapeutic window when compared to the free drug. Finally, NLC 21–04 showed a marked tumor growth reduction while being safe in an in ovo tumor model, highlighting the therapeutic potential of the developed nanoparticles against triple negative metastatic breast cancer.

Development of Calcium-Dependent Phospholipase A2 Inhibitors to Target Cellular Senescence and Oxidative Stress in Neurodegenerative Diseases.

Significance: Cellular senescence is a critical process underlying aging and is associated with age-related diseases such as Alzheimer's disease. Lipids are implicated in cellular senescence. Fatty acids, particularly eicosanoids, have been associated with various forms of senescence and inflammation, and the associated reactive oxygen species production has been proposed as a therapeutic target for mitigating senescence. When overactivated, calcium-dependent phospholipase A2 (cPLA2) catalyzes the conversion of arachidonic acid into eicosanoids such as leukotrienes and prostaglandins. Recent Advances: With a growing understanding of the importance of lipids as mediators and modulators of senescence, cPLA2 has emerged as a compelling drug target. cPLA2 overactivation plays a significant role in several pathways associated with senescence, including neuroinflammation and oxidative stress. Critical Issues: Previous cPLA2 inhibitors have shown potential in ameliorating inflammation and oxidative stress, but the dominant hurdles in the central nervous system-targeting drug discovery are specificity and blood-brain barrier penetrance. Future Directions: With the need for more effective drugs against neurological diseases, we emphasize the significance of discovering new brain-penetrant, potent, and specific cPLA2 inhibitors. We discuss how the recently developed Virtual Synthon Hierarchical Enumeration Screening, an iterative synthon-based approach for fast structure-based virtual screening of billions of compounds, provides an efficient exploration of large chemical spaces for the discovery of brain-penetrant cPLA2 small-molecule inhibitors. Antioxid. Redox Signal. 00, 000-000.

Opportunities and Challenges of Arginase Inhibitors in Cancer: A Medicinal Chemistry Perspective.

The overexpression of two arginase (ARG) isoforms, ARG1 and ARG2, contributes to the onset of numerous disorders, including cardiovascular and immune-mediated diseases, as well as tumors. To elucidate the specific roles of ARG1 and ARG2 without interfering with their physiological functions, it is crucial to develop effective ARG inhibitors that target only one isoform, while maintaining low toxicity and an adequate pharmacokinetic profile. In this context, we present a comprehensive overview of the different generations of ARG inhibitors. Given the general lack of selectivity in most existing inhibitors, we analyzed the structural features and plasticity of the ARG1 and ARG2 binding sites to explore the potential for designing inhibitors with novel binding patterns. We also review ongoing preclinical and clinical studies on selected inhibitors, highlighting both progress and challenges in developing potent, selective ARG inhibitors. Furthermore, we discuss medicinal chemistry strategies that may accelerate the discovery of selective ARG inhibitors.

Prediction of SHP2-E76K binding sites based on molecular dynamics simulation and Markov algorithm

SHP2-E76K, a mutant encoded by the PTPN11 gene, was associated with various solid tumors, such as lung cancer, glioblastoma, and intellectual disability. SHP2-E76K has become potential drug targets, while there was no effective inhibitor against the mutant currently. At present, the crystal complex structure of SHP099 with SHP2-E76K has been reported in the RCSB PDB protein data bank, however, the dynamic structure of SHP099 binding to the active center of SHP2-E76K protein was still lacking. Therefore, this study used molecular dynamics simulation and Markov model to characterize the kinetics of the inhibitor SHP099 with SHP2-E76K enzyme and to determine the active binding site, which would give a hint of a vital enzyme-substrate interaction in atomistic detail that proposed the potential to be applied for the discovery of more effective SHP2-E76K inhibitors and, in broader terms, dynamic protein-drug interactions.

Discovery and synthesis of novel phenoxyacetate ester Schiff base α-glucosidase inhibitors

A phenoxyacetate ester Schiff base lead compound 4a (ZINC20073984) was firstly discovered through molecular docking screening and molecular dynamics (MD) simulation, which could be used as an α-glucosidase (PDB: 3A4A) inhibitor. Then a series of α-glucosidase inhibitors 4b-4r with novel structures were designed and synthesized with the lead ZINC20073984 as a template. The results of in vitro α-glucosidase inhibitory activity show that the synthesized phenoxyacetate ester Schiff base compounds 4e, 4o-4r (IC50 values range from 5.44 ± 0.52 μM to 33.67 ± 9.1 μM) exhibit good activity. Among them, ethyl (Z)-2-(2,4-dinitro-5-(2-(1-(2,4,6-trimethoxyphenyl) ethylidene) hydrazineyl) phenoxy) acetate (4r) and ethyl (Z)-2-(2,4-dinitro-5-(2-(1-(1-(4-ethoxyphenyl) ethylidene) hydrazineyl) phenoxy) acetate (4p) exert the best inhibitory activity, with IC50 values of 5.44 ± 0.52 μM and 5.80 ± 1.4 μM, respectively, which are superior to the standard drug acarbose (IC50 = 8.36 ± 0.02 μM). Molecular docking results indicate that the good inhibitory activity of 4r and 4p may be attributed to multiple hydrogen-bonding interactions with the α-glucosidase. Furthermore, the drug-likeness of all synthesized compounds was evaluated using the pkCSM tool, and ADMET predictions were conducted for compound 4r. The results demonstrated that all compounds follow Lipinski’s rules, and 4r possesses favorable pharmaceutical properties. In an in vitro cytotoxicity assay, the most potent 4r shows non-cytotoxicity to the 3T3 cells with an CC50 value > 40 µM. In both antioxidant and anti-cancer capacity assays, compound 4r has demonstrated promising potential. The results of this study might be helpful in the discovery of new drugs for the treatment of diabetes mellitus type-2 and bladder cancer.

Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858. By targeting the metal pocket of PDE1, a lead compound 3f was obtained, exhibiting an IC50 value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.

Discovery and binding mode of small molecule inhibitors of the apo form of human TDO2

Tryptophan-2,3-dioxygenase (TDO2) and indoleamine-2,3-dioxygenase (IDO1) are structurally distinct heme enzymes that catalyze the conversion of L-tryptophan to N-formyl-kynurenine, and play important roles in metabolism, inflammation, and tumor immune surveillance. The enzymes can adopt an inactive, heme-free (apo) state or an active, heme-containing (holo) state, with the balance between them varying dynamically according to biological conditions. Inhibitors of holo-TDO2 are known but, despite several advantages of the heme-free state as a drug target, no inhibitors of apo-TDO2 have been reported. We describe the discovery of the first apo-TDO2 binding inhibitors, to our knowledge, and their inhibition of cellular TDO2 activity at low nanomolar concentrations. The crystal structure of a potent, small molecule inhibitor bound to apo-TDO2 reveals its detailed binding interactions within the large, hydrophobic heme binding pocket of the active site.

Discovery of α-amylase and α-glucosidase dual inhibitors from NPASS database for management of Type 2 Diabetes Mellitus: A chemoinformatic approach.

Postprandial hyperglycemia, typical manifestation of Type 2 Diabetes Mellitus (T2DM), is associated with notable global morbidity and mortality. Preventing the advancement of this condition by delaying the rate of glucose absorption through inhibition of α-amylase and α-glucosidase enzymatic activities is of utmost importance. Finding a safe antidiabetic drug is essential since those that are currently on the market have drawbacks like unpleasant side effects. The current study utilized computer-aided drug design (CADD), as a quick and affordable method to find a substitute drug template that can be used to control postprandial hyperglycemia by modulating the activity of α-amylase and α-glucosidase enzymes. The Natural Products Activity and Species database (NPASS) (30,926 compounds) was screened in silico, with a focus on evaluating drug-likeness, toxicity profiles and ability to bind on a target protein. Two molecules NPC204580 (Chrotacumine C) and NPC137813 (1-O-(2-Methoxy-4-Acetylphenyl)-6-O-(E-Cinnamoyl)-Beta-D-Glucopyranoside) were identified as potential dual inhibitors for α-amylase and α-glucosidase with free binding energies of -14.46 kcal/mol and -12.58 kcal/mol for α-amylase, and -8.42 kcal/mol and -8.76 kcal/mol for α-glucosidase, respectively. The molecules showed ionic, H-bonding and hydrophobic interactions with critical amino acid residues of both enzymes. Moreover, 100 ns molecular dynamic simulations showed that both molecules are stable on the receptors' active sites based on root mean square deviation (RMSD), root mean square fluctuation (RMSF), and the Generalized Born surface area (GBSA) energy calculated. The two compounds are thus promising therapeutic agents for T2DM that merit further investigation due to their excellent binding energies, encouraging pharmacokinetics, toxicity profiles, and stability as demonstrated in simulated studies.