Letters in Drug Design & Discovery - Volume 21, Issue 10, 2024

Background: Pyrimidine and hydrazones are well known for their therapeutic applications. Objective: To investigate the antioxidant activities of compounds having pyrimidine and hydrazone motifs in hope of finding molecules with robust antioxidant activities. Methods: Hydrazones were obtained by condensing pyrimidine hydrazine with aromatic ketones. The structures of these compounds were established on the basis of NMR, FTIR and mass spectral data analysis. Results: All compounds were assessed for their antioxidant potential against DPPH, hydrogen peroxide, nitric oxide and superoxide free radicals. Conclusion: A series of twelve 2-(1-(substituted phenyl)ethylidene)-1-(4,6-dimethylpyrimidin-2-yl)hydrazines was synthesized and compounds 6d, 6e, 6h, and 6j found to have good antioxidant activities.

Introduction: The novel coronavirus disease (COVID-19) is a viral disease caused by severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2). The development of antiviral drugs has enhaced treatment of COVID-19. SARS-CoV-2 main protease (M^pro) is a key enzyme responsible for viral replication and transcription. This study aimed to identify new natural structures for the design of SARS-CoV-2 M^pro inhibitors. Methods: In this present work, The CDOCKER protocol and scoring functions were validated. The validated docking-based virtual screening approach was then employed to search the in-house database of natural compounds for potential lead compounds as SARS-CoV-2 M^pro inhibitors. The top 3 compounds were further biologically evaluated in vitro. Results and Discussion: Docking studies of the known ligand GC-376 led to results consistent with cocrystallized data (PDB ID: 7D1M). Additionally, the effectiveness of docking scoring functions was validated by using the training set consisting of 15 active compounds and 15 inactive compounds. Then, the in-house database of natural compounds (overall 34,439 natural compounds) was subjected to dockingbased virtual screening resulting in the identification of the top 100 compounds having relatively better docking scores. Among them, the highest ranking 3 compounds (W-1, W-2, and W-3) were biologically evaluated in vitro for their inhibitory activity against SARS-CoV-2 M^pro, and compound W-1 was identified as the most potent SARS-CoV-2 M^pro inhibitor with an IC50 value of 63 ± 3 μM. Interestingly, it appeared that the in vitro activities of compounds W-1, W-2, and W-3 were in agreement with their molecular modeling data. Conclusion: Our results provided a useful reference for the discovery of novel natural SARS-CoV-2 M^pro inhibitors by virtual screening.

Background: Among the seven human sirtuins SIRT1-7, SIRT3 is not lesser functionally understood. However, the identification of its inhibitors has not been quite a success. Objective: In the current study, we intended to see if we were able to develop cyclic tripeptide-based human SIRT3 inhibitors that would harbor the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead N^e-thioacetyl-lysine. Methods: In the current study, we prepared the corresponding N-terminus-to-side chain cyclic analog of two of our previously reported linear tripeptidic human SIRT3 inhibitors whose chemical structures both harbor the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead N(epsilon)-thioacetyl-lysine at the central position and subjected the analogs to the same sirtuin inhibition assay under the same assay condition as those employed previously in our laboratory for the two parent linear tripeptidic SIRT3 inhibitors. Results: We found that analog 2 exhibited an enhanced SIRT3 inhibitory potency than its linear tripeptidic parent (i.e. compound 2a) and displayed a SIRT3 inhibitory IC50 value of ~340 nM which is smaller than its inhibitory IC50 values against other sirtuins with the following folds: ~2-fold versus SIRT1, ~7.7- fold versus SIRT2, and >68-353-fold versus SIRT5-7. Conclusion: The successful identification of the human SIRT3 inhibitor 2 in the current study would help the further functional dissection and pharmacological exploitation of the SIRT3 deacetylation reaction.

pyridone nucleus is an important scaffold present in various compounds with diverse pharmacological activity. Among the reported 2-pyridone analogs, the majority of the compounds either have a substituted ring system or a fused ring system. Till now, several derivatives have been reported by different researchers for their antimicrobial activity, anticancer activity, antiviral activity, antioxidant activity, anti-hepatitis virus activity, and anti-allodynia and anti-obesity activities. In this review, we have attempted to compile synthetic methods of 2-pyridone ring by ring cyclization along with pharmacological aspects related to various synthesized derivatives of the 2-pyridone nucleus.

In recent years, substantial modelling breakthroughs have been achieved in artificial intelligence due to new algorithms, improved computer power, and expanded storage capacity. These factors have made it possible to process large amounts of data in a short amount of time. By using quantum computing in conjunction with deep learning models, it has been possible to explain the characteristics of ligands and their interactions with biological targets. This contributes to the process of ligand identification and ultimately results in the optimization of drug design. This review explains the extensive use of quantum deep learning in the development of drug design from traditional to quantum-powered deep learning neural networks that cover some domains like variational quantum Eigen solver, variational quantum circuits, quantum convolutional deep neural networks, QC-based deep neural networks for QSAR, as well as quantized generative models for the discovery of small drug molecules. Quantum computing can execute incredible computational work tenfold faster than current technology, transforming drug design, development, and post-marketing surveillance. This will reduce the time and resources needed to develop a medicine. Scientific research is moving toward quantum computing since it is anticipated that QC-based deep learning technologies can predict and mimic the characteristics, structures, and activities of molecules more efficiently than different ML techniques or conventional computers.

Dementia is a devitalising decline in neurological acuity, which burdens both high- and lowincome countries due to poor diagnostic systems and high healthcare costs. A growing population and rises in deleterious environmental and genetic anomalies aggravate new and aggressive cases of dementia and neurodegenerative disorders. The unparalleled capability of medicinal plants is constantly explored in treating neurological disorders, and some of these phytocompounds are used for treating diseases. However, some of these metabolites are neurotoxic and disrupt DNA polymerase functions. They possess lifethreatening side effects and are unable to prevent disease progression. Therefore, it is important to focus on discovering novel compounds from new medicinal plants. Our review encompasses some medicinal plant metabolites recently explored in treating this disease. We also summarized the molecular mechanism of action as determined in in-vitro: the toxic dose, nootropic and neuroprotective effects on neurophysiology and neurotransmitter levels, and the antioxidant effects.

The study of carbon-based materials and nanoparticles is currently an exciting field of study in the domain of material science. One of the most prominent of these materials is graphene, along with its related components graphene oxide and reduced graphene oxide. A single-layer, twodimensional nanomaterial called graphene (GN) is employed in many different industries, such as electronics and biology. Graphene is a remarkable two-dimensional substance that has earned the title of "wonder material." Its remarkable electrical, optical, thermal, and mechanical qualities have attracted significant attention. Graphene's intriguing characteristics have led to its integration into numerous biosensing applications. Graphene possesses remarkable chemical, electrical, and physical qualities. The distinctive properties of graphene, particularly its electrical conductivity, large surface area, and significant electron mobility, are focusing more attention on applications in biomedicine that facilitate easier health monitoring. Biosensors with high sensitivity and precision can enhance patient care, and offer an opportunity for an early illness diagnosis and clinical pathogen identification. Additionally, a wide range of biological molecules, including glucose, hydrogen peroxide, cholesterol, dopamine, etc., can be detected using graphene-based biosensors. This study evaluates contemporary developments regarding graphene-based biosensors and their prospects and difficulties in this rapidly developing profession in the coming era. Graphene-based nanomaterials are appropriate to be employed in various biological and sensory contexts, including medicine and gene transfer, because of their unusual topologies and extraordinary properties. Graphene's outstanding characteristics enable biosensing applications to obtain the appropriate sensitivity, selectivity, and repeatability for a range of targets.

Background: Type 2 diabetes mellitus continues to pose a threat to the existence of the human race. The increasing number of diabetic subjects can be effectively controlled by targeting enzymes responsible for high blood glucose levels. Xanthones are a class of phytochemicals that possesses promising pharmacological potentials. Objective: This study identified fructose 1,6-biphosphatase (FBPase) inhibitors by exploring xanthones isolated from African medicinal plants through ensemble docking, molecular dynamics simulation and density functional theory methods. Methods: The study used ensemble docking, molecular dynamics simulation and density functional theory (B3LYP/6-3G (d,p) basis set) and ADMET methods to select lead compound that may be effective as fructose-I,6-biphosphatase inhibitor. Results: The ensemble docking results identified globulixanthone C (-10.0 kcal/mol), 1-Isomangostin (- 9.0 kcal/mol), laurentixanthone A (-9.0 kcal/mol), bangangxanthone A (-8.9 kcal/mol) and staudtiixanthone B (-8.8 kcal/mol) as potential inhibitors of fructose-1,6-biphosphatase. Molecular dynamics studies showed the xanthones established good binding mode and their binding energy ranged from -74.057 to 53.669 kJ/mol. Also, the electronic and ADMET studies of the xanthones elucidated their excellent pharmacological potential. Conclusion: The study identified xanthones as potential fructose-1,6-biphosphatase inhibitors. The ligands' binding energy and MMPBSA calculations supported their possible inhibitory property. Also, the ADMET properties estimated show the ligands as suitable drug candidates as fructose-1,6-biphosphatase inhibitors. Further in vitro and in vivo investigation of the hit molecules is necessary to develop new FBPase inhibitors.

Background: Cancer is a group of illnesses characterised by the impartial increase and unfolding of somatic cells. A variety of natural compounds, such as curcumin, zingiberine and their composites, and synthetic organic derivatives of imidazole, benzothiazole, oxadiazole, quinazoline etc., have been developed as anticancer agents. But many of these show various side effects, drug resilience, and toxicity to the normal cells of the host body. Therefore, there is still demand to develop new synthetic derivatives to improve their pharmacological profile. Objective: The Aim of this study is to understand the binding mode and to check the drug likeliness of numerous 1,3,4-oxadiazole derivatives as EGFR inhibitors for the treatment of cancer. The objective of the study is to screen newly designed derivatives of 1,3,4-oxadiazole using molecular docking and ADMET studies as EGFR inhibitors. Methods: In silico docking studies were performed using AutoDockVina software, and compounds were further studied for ADME and toxicity using SwissADME and pkCSM software, respectively. Results: Considering the docking results, pharmacokinetic behaviour and toxicity profile, eight derivatives (derivatives 2,3,4,5,10,13,16, and 17) showed potential as EGFR inhibitors. Conclusion: Compounds 2 and 3 showed the highest binding affinity in the pocket of EGFR and also displayed a better pharmacokinetic profile. Therefore, these derivatives can be used in the management of cancer and can be taken further for wet-lab studies.

Background: The Amyotrophic lateral sclerosis (ALS) is a degenerative and most frequent motor neuron disease characterized by the progressive impairment of upper and lower motor neurons. The treatment of the disease is still palliative and limited to the use of only two drugs, riluzole and edaravone, which only prolong survival by a few months. Taking into account the low number of therapy available for this disease, identification of novel therapeutic strategies for ALS is urgently needed. The superoxide dismutase 1 (SOD1) was the first gene in which mutations were found to be causative for the neurodegenerative disease and has been used as a promising target for the ALS treatment. Methods: In this work we used powerful computational tools (in silico method) such as Ligand-based Virtual Screening (SBVS), docking and molecular dynamics techniques to collaborate with the discovery of new candidates for more potent drugs to be used in the ALS disease treatment. Results: Compound 1 shows good stability in the active site of the SOD1 enzyme, with an intermolecular interaction energy of -154.80 kcal/mol. In addition, the presence of some amino acids such as Glu24, Glu21, Pro28, Lys23 and Lys30 is important for to maintain stability of this compound inside SOD1. Conclusion: This study was essential due to a low number of therapy available for this disease until the moment. With this study, it was possible to observe that Compound 1 is the most promising for the design of SOD1 mutant enzyme potential inhibitors. However, experimental tests in the SOD1 mutant to validate the inhibitory effect of Compound 1 will be required.

Aims: A computational approach has been adopted to find therapeutically potent herbal compounds with anti-TB properties. Background: The second largest cause of death globally is Mycobacterium tuberculosis. Considering that the BCG vaccine is only marginally effective. This study has focused on enoyl- (acyl carrier protein)- reductase (InhA), one of the important enzymes in M. tuberculosis's type II fatty acid (mycolic acid synthesis) biosynthesis pathway. Bioinformatics-based tools have been used to explore therapeutically sound phytocompounds against InhA. Objective: To conduct an insightful study using bioinformatics-based tools to explore phytocompounds originating from different medicinal plants which would act as potent inhibitors of enoyl - (acyl carrier protein)- reductase (InhA) to obstruct the growth of M. tuberculosis. Method: Molecular docking (using EasyDockVina) has been used for screening the 150 phytocompounds against Enoyl - (acyl carrier protein)- reductase (InhA). AMDET analysis was performed using DruLito and protox II to test the drug-likeness properties of phytocompounds. Result: From the results of molecular docking and two-dimensional interaction, it is concluded that Licoflavone B, Tembaterine, Colubrine and Shinpterocarpin are the potent inhibitors of InhA. Conclusion: According to this study, Licoflavone B, Tembaterine, Columbin, and Shinpterocarpin have positively passed AMDET screening and have high docking scores. These phytocompounds can be considered safe drug candidates against InhA of Mycobacterium tuberculosis.

Aims: To investigate novel isoxazole amide SMYD3 inhibitors as adjuvant anticancer agents for multiple cancers. Background: SET and MYND Domain-Containing Protein 3 is a hopeful therapeutic target for breast, liver, colon, and prostate cancer. Objective: Novel SMYD3 inhibitors were predicted by the 3D-QSAR models. Methods: In this present work, 3D-QSAR, molecular docking and molecular dynamics (MD) simulations were performed on a series of isoxazole amides-based SMYD3 inhibitors. Results: Molecular docking revealed residues important to protein-compound interactions, indicating that SMYD3 inhibitors have a strong affinity with and bind to key protein residues such as TYR239, MET190, LYS297 and VAL368. The molecular docking results were further validated by molecular dynamics simulations. Conclusion: The above information provided significant guidance for the design of novel SMYD3 inhibitors.

Background: The increasing prevalence of depression has become a global health issue. Currently approved anti-depressive including 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), triple reuptake inhibitors (TRIs) and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists have limited effects because of their insufficient efficacy and/or slow onset of action. Developing multifunctional antidepressants that can modulate 5-HT, DA, NE, and NMDA simultaneously can potentially overcome the current drug defects. Objective: This study aimed to explore leads for the development of multi-functional anti-depressive agents that simultaneous triple reuptake inhibitory and NMDA-GluN2B receptor antagonistic activities. Methods: Potential leads were screened virtually from the TCMSP database based on the 3DPharmacophore model of TRIs followed by the molecular docking into NMDA-GluN2B receptor, BBB score, and the in silico toxicity evaluation. The biological activities of discovered leads on 5-HT, NE, and DA reuptake and their effect on the NMDA-GluN2B receptor were evaluated via radio-labeled neurotransmitters and competition radio-ligand binding experiment with [³H] ifenprodil, respectively. Lastly, the antidepressant effect of these potential leads was determined in vivo through the forced swim test in mice. Results: Two compounds were attained as potential leads after the aforementioned experiments. Further in vitro biological evaluation identified Hit-2 as a promising lead that exerted favorable triple 5- HT/DA/NE reuptake inhibitory activity (66.98% inhibition rate at 10 μM against hNET, 73.01% inhibition rate at 1 μM against hDAT and 86.27% inhibition rate at 1 μM against hSERT), as well as potent NMDA-GluN2B receptor antagonistic activity (Ki=115.73 ± 3.54 nM). The antidepressant activity of Hit- 2 was confirmed through in vivo experiments Conclusion: Hit-2 not only simultaneously inhibited the reuptake of 5-HT, DA, and NE, and acted as an NMDA-GluN2B receptor antagonist in vitro but also showed in vivo antidepressant activity. These findings may serve as a structural basis for the further development of multi-functional anti-depressive agents.

Objective: This study aimed to discover a novel active compound capable of effectively inhibiting JAK3/STAT1 and CYP3A4 using molecular modelling techniques, with the goal of treating autoimmune diseases such as cancer and specifically rheumatoid arthritis. The study involved modelling compounds derived from pyrazolopyrimidine, followed by screening methods to identify the most promising compounds. Moreover, this study seeks to identify potential compounds that can inhibit JAK3/STAT through molecular modelling techniques and validate the stability and affinity of the predicted molecule. Methods: Various molecular modelling techniques were employed to identify potential compounds and assess the stability and affinity of the predicted molecule. A pharmacophore hypothesis was developed to obtain crucial information about the experimental series of pyrazolopyrimidine studied, which served as the basis for designing new molecules. Additionally, ADMET was utilized to predict and evaluate the pharmacokinetic properties and potential toxicity of the compound prior to synthesis or utilization. To determine the essential residues involved in the interaction between the molecule and the target JAK3 protein, the covalent docking method was applied. We further validated the binding stability of the JAK3 protein with the ligands ZINC62162141 and Tofacitinib, both of which have been approved by the FDA for JAK3/STAT inhibition., using DFT/B3LYP/6-31G molecular dynamics simulations lasting 1000 ns and MM/GBSA. Results: During the study, we identified compounds that displayed notable activity against JAK3/STAT, specifically those containing thiadiazol, oxadiazol, and chlorophenyl groups. Additionally, the pharmacophore model, ADRRR_1, exhibited promising potential for predicting new molecules. The predicted compound, ZINC62162141, demonstrated favourable ADMET properties, including inhibition of CYP3A4. Furthermore, we assessed its binding stability to the target protein and determined its affinity for the protein-ligand complex using MMGBSA. Conclusion: The results of this study suggest that the compounds identified have the potential to be promising candidates for inhibiting JAK3/STAT and CYP3A4, offering potential therapeutic benefits for the treatment of rheumatoid arthritis. These findings provide a foundation for subsequent experimental validation and the development of novel drugs in this field.

Aims: Validation of mesalamine (MS) as a potential therapeutic agent in treating diabetic wound (DW) healing using in silico approach. Background: Diabetic wound (DW) is a serious consequence of diabetes that frequently results in the amputation of the affected organ. Maggot therapy, pressure off-loading, surgical intervention, glucose control, hyperbaric oxygen therapy, wound debridement, and other treatments are currently available for DW. However, the majority of people do not meet all DW requirements due to significant pathology and the high expense of the solutions. Objective: To address the issues with current conventional therapy, we reasoned that repurposing existing medication (MS) to a target receptor that plays a significant role in the progression of DW might be advantageous. Mesalamine (MS), also known as Mesalazine or 5- Aminosalicylic acid, is an aminosalicylate anti-inflammatory used to treat inflammatory bowel disease (IBD), ulcerative colitis (UC), inflamed anus or rectum. The complicated pathophysiology of DW, which includes prolonged inflammation, increased infection, decreased cell proliferation, and migration, is a serious issue. As a result, we chose the MMP-9, TNF-α, MurC, ParE, and GSK-3β receptors as a universal target for treating the complex pathogenesis of DW. The use of MS as a therapeutic modulator on MMP-9, TNF-α, MurC, ParE, and GSK-3β receptors was studied in the current hypothetical investigation. Methods: Computational studies such as molecular docking and MMGBSA were performed by using the Schrödinger suite. Results: Computational investigations, such as molecular docking and MMGBSA were used to test our theory. It is clear from the in silico methods that MS has a higher binding affinity for the designated receptors. Hence, it is predicted that MS may be a good therapeutic agent to use in the treatment of DW. Conclusion: As a result of our findings, MS appears to be a unique therapeutic drug for the treatment of DW. However, further studies are highly required to take MS into clinical use.

Background: Diabetes is a multifaceted metabolic condition defined by postprandial hyperglycemia with perturbances in the majority of the metabolic systems in the human body. α-amylase is a key enzyme present in pancreatic juice and saliva that converts one of the common food sources i.e., starch molecules into absorbable molecules and raises plasma glucose levels. Reducing starch digestion by the inhibitors of starch hydrolyzing enzymes could be an intriguing strategy for improved postprandial hyperglycemia management. Objective: The present research work was undertaken to evaluate the inhibition potential of natural inhibitors of α-amylase from Trichosanthes dioica (pointed gourd) and Moringa oleifera (moringa leaves) extracts in vitro. Furthermore, in vivo cytotoxicity assessment was also conducted through brine shrimp lethality bioassay. Methods: Different organic solvents (namely acetone, ethanol, and methanol) were used to isolate plant extracts. DNS (3,5-dinitrosalicylic acid) was used to conduct the α-amylase inhibition assay. The safety of the natural inhibitors was determined by the most common technique i.e, brine shrimp lethality bioassay. Results: Among all the different organic solvent extracts, pointed gourd and its peel exhibited the highest α-amylase inhibition activity (64.03 ± 7.33–69.40 ± 9.38%) which is very close to standard α-amylase inhibitor acarbose (72.34 ± 4.23%) whereas moringa leaves showed moderate inhibition activities (59.10 ± 5.25–62.03 ± 1.77%). The cytotoxicity of pointed gourd and its peel was higher while moringa leaves demonstrated lower toxicity. Conclusion: Considering the inhibition rate and cytotoxicity, pointed gourd ethanol extract (Inhibition: 67.43 ± 11.80%; Cytotoxicity: 209.98 μg/mL) would be the best candidate for managing postprandial hyperglycemia.

Background: Hepatic and gastric diseases are two of the most common ailments in people. Numerous researches have been conducted to evaluate the effectiveness of herbal remedies in the treatment of hepatitis and stomach ulcers. Objective: The study aimed to determine the antiulcer and hepatoprotective activities of Euphorbia hirta petroleum ether, chloroform and ethanolic extracts on paracetamol-induced ulcerated Wistar rats. Materials and Methods: Euphorbia hirta was collected from the area of Salem, Tamil Nadu, India. The air-dried whole plant was crushed, and 500 g of the powder and petroleum ether, chloroform and ethanol were used for continuous extraction by the Soxhlet device. Phytochemical analysis of the extract was done by conventional and GC-MS analysis. Nine sets of six male Wistar rats, each weighing between 150 and 200 g, were used in this study. The standard control group, Group I, received only 1% v/v tween 80. Group II, negative control, received saline (1 ml/kg p.o.). Group III animals were given silymarin (200 mg/kg p.o.) and paracetamol (2 g/kg), which served as the standard of care. Animals in groups IV, V, VI, VII, VIII, and IX received two separate doses (200 and 400 mg/kg) of petroleum ether, chloroform, and ethanolic extracts of Euphorbia hirta L. Liver tissue was taken for histological investigation and placed in a 10% formalin solution. The liquid supernatant of liver cells was used to measure antioxidant parameters, such as catalase, superoxide dismutase, and LPO. Results: Phytochemical and GC-MS examination confirmed Euphorbia hirta extracts to have different biologically active phytoconstituents, like alkaloids, carbohydrates, glycosides, phenolic, flavonoids, tannin, sterols and alkaloids. Euphorbia hirta has been found to significantly protect against paracetamolinduced ulcer and hepatotoxicity compared to the negative control. A significant (p < 0.001) reduction in SGPT, SGOT, ALP, DB and TB levels in the EEEH 400 mg/kg extract-treated group was observed compared to the paracetamol group. The PEEH extract exhibited no significant decrease in all biochemical parameters compared to the negative control. However, the standard drug showed a significant (p < 0.001) decrease when compared to the negative control. SGPT, ALP, and DB levels demonstrated a significant (p < 0.01) reduction with EEEH 200 mg/kg. The PEEH extract induced no significant decrease in all biochemical parameters compared to the negative control, and the chloroform extract of 200 mg/kg showed a less significant (p < 0.05 & p < 0.01) difference compared to the negative control. The histopathology study confirmed EEEH 200 mg/kg to show good hepatoprotective activity. Conclusion: The findings have demonstrated Euphorbia hirta ethanolic extract to have effective antiulcer capabilities, and a decrease in LPO activity along with an increase in SOD, CAT, and LPO content have been observed, thereby leading to reduced oxidative stress. The antioxidant activity of Euphorbia hirta extract as a free radical scavenger and the hepatoprotective effect of the ethanolic extract have been indicated by the results of liver enzymes, DB and TB, and histology of liver tissue. More research is needed to recommend Euphorbia hirta as an effective supplement to treat paracetamol-induced ulcers and hepatotoxicity.

Background: The pre-existing EGFR (Epidermal Growth Factor Receptors) inhibitors (Gefitinib, Afatinib and osimertinib) show significant resistance after one year of EGFR therapy in NSCLC (Non-small cell lung cancer) patients. With the aim of overcoming the resistance problem associated with a current therapeutic regimen, there is an imperative need for the development of novel 4- anilinoquinazoline derivatives that are specifically designed for resistance cases of NSCLC patients. Objective: We designed and synthesized eighteen 4-anilinoquinazolines derivatives as a novel scaffold and evaluated their anti-cancer potential against different NSCLC cell lines. Methods: Molecular docking study of designed compounds were performed on Glide v5.8 (Schrodinger, LLC, New York, NY). Synthesis of 4-anilinoquinazoline derivatives were performed, based on the docking score and was characterized by various spectroscopic methods. Further, in vitro anti-cancer activity was performed using MTT assay on different cancer cell lines. Results: Molecular docking analysis [EGFR^T790M mutant (4I22)] indicated that most of these analogs (6g, 6j, 6l, 6m and 6o) were found to be higher docking scores than gefitinib. Furthermore, spectral analysis revealed that the designed compounds were synthesized successfully. The compounds 6a, 6d, 6g, 6i, 6j and 6m were identified as the potent inhibitors against (A431, H1975, A549) cell lines as compared to reference standard gefitinib. Excitingly, compound 6j (with IC50 values of 4.88 ± 0.13, 4.38 ± 0.08 & 11.97 ± 0.14 μM) was identified as the most potent inhibitor for (A431, H1975, A549) cell lines. Conclusion: The study suggested that the six derivatives showed significant therapeutic potential against different NSCLC cell lines as compared to reference standard gefitinib.

Objective: This article aimed to identify the bioactive compounds present in the brown algae Sargassum tenerrimum using TLC and HPTLC fingerprinting analysis and followed in silico molecular docking against a potential target of anxiety, depression, and cognitive disorder with identified compounds. Methods: Bioactive compounds were identified from the methanolic extract of Sargassum tenerrimum through TLC and HPTLC fingerprinting analysis. In silico molecular docking against a potential target of anxiety, depression, and cognitive disorder was performed on the latest version of AutoDock Vina v.1.2.0 software. The pharmacokinetic profile and possible bioactivities of the compounds were predicted using SwissADME. Results: Fucoxanthin, β-Cryptoxanthin, and Canthaxanthin were identified from the brown algae Sargassum tenerrimum through TLC and HPTLC fingerprinting analysis. Fucoxanthin showed the highest fitness score of -9.7 kcal/mol, -9.6 kcal/mol, and -9.7 kcal/mol against the target protein GABA-A, 5ht2c, and AchE, respectively. β-Cryptoxanthin showed the highest fitness score of -9.4 kcal/mol against target SERT compared with Fucoxanthin and Canthaxanthin. Canthaxanthin exhibited the highest fitness score- 7.5 kcal/mol, -9.0 kcal/mol, -9.7 kcal/mol, -9.1 kcal/mol, -9.1 kcal/mol, -7.4 kcal/mol, -7.9 kcal/mol and - 7.6 kcal/mol against the target receptor trkB, 5ht1A, D2, DAT, MOA-A, COMT, NMDA and 7nAchR respectively on the comparing with Fucoxanthin and β-Cryptoxanthin. Conclusion: In silico docking and ADME analysis concluded that the canthaxanthin acted through various targets and was safer than the fucoxanthin and β-Cryptoxanthin. Hence, canthaxanthin can be the best potential compound in the therapy of neuropsychological disorders.

Background: Acute myeloid leukemia (AML) is the most common type of blood cancer. Fmslike tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinase family. Overexpression of FLT3 was found in 70-100% of patients with acute myeloid leukaemia. FLT3 internal tandem duplication alteration (ITD) and the tyrosine kinase domain (TKD) are the most common molecular alteration in AML, and FLT3 has become a promising drug target for AML. Objective: A series of 6-phenylisoxazolo[3,4-b]pyridin-3-amine derivatives F1–F15 with amide bonds as FLT3 inhibitors were designed and synthesized in order to find a new lead compound to treat AML. Methods: We designed an original scaffold-hopping protocol by combing the RECAP tool with the Gilde-based Core-hopping tool to design novel FLT3 inhibitors based on Linifanib. Inhibitors assembled were ranked by the docking scores generated by Glide. Compounds undisclosed among the top 10 were selected to design a series of 6-phenylisoxazolo[3,4-b]pyridin-3-amine derivatives as FLT3 inhibitors. The kinase inhibitory activities of the fifteen compounds were assayed on FLT3 and FLT3-ITD. The antitumor activities of the structurally modified compounds F1–F15 were evaluated against MOLM-13 and MV4-11, typical FLT3-dependent human AML cells carrying FLT3-ITD mutants and the FLT3- independent human cervical carcinoma cell line HL-60 (harboring wide-type FLT3). Results: Structure-activity relationship (SAR) analysis showed that F14 could inhibit FLT3 and FLT3- ITD by 52% and 45.55%, respectively, at the concentration of 1 mM. F14 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines, MOLM-13, and MV4-11 (harboring FLT3-ITD mutant) with IC50 values of 2.558 μM and 1.785 μM, respectively. Conclusion: F14 could be used as a novel lead compound to further develop FLT3 inhibitors against AML with FLT3-ITD mutant.

Introduction: Pesticides have lethal properties, capable of controlling or eliminating a living organism; they block the organisms' vital metabolic processes. They cause serious problems for human health, as they are highly toxic. The most used pesticides that are considered toxic are known as organophosphothioates (OP/P=S) in their commercialized form and organophosphates (OP/P=O) in their active form. These compounds have been the subject of studies on their metabolism and toxicology. According to research, these pesticides' toxicity is increased when oxidative metabolic desulfurization reactions occur, with the P=S bond being transformed into a P=O bond. This toxicity is due to the ability of OP/P=O species to inhibit the human acetylcholinesterase enzyme (HssAChE). Methods: To study the oxidative biotransformation of OP/P=S pesticides and the inhibition of the HssAChE enzyme by OP/P=S and OP/P=O using the molecular docking technique and QM/MM calculations. Results: The theoretical results showed that parathion is the compound with the greatest capacity to transform its P=S bonds into P=O bonds, thus forming the active paraoxon metabolite in the oxidative biotransformation process. In the HssAChE inhibition by OP/P=S and OP/P=O, our results showed that of all the compounds investigated, those with the highest inhibitory activities are parathion, paraoxon, malathion, diazoxon, chlorpyrifos and omethoate. Conclusion: This study was essential due to the lack of information in the literature about the oxidative biotransformation process of OP/P=S pesticides and the ability of these compounds to inhibit HssAChE. With this study, it was possible to observe that, in the oxidative biotransformation, chlorpyrifos and parathion have greater capacities to transform into their active metabolites and in the inhibition of the HssAChE enzyme, it was possible to observe that not all OF/P=O are the ones with the highest abilities to inhibit the HssAChE enzyme.

Introduction: Natural compounds obtained from marine algae, especially Rhodophyta are now being investigated for various biological activities. However, the antimicrobial activity and toxicity profile of compounds present in these algae isunderexplored. Objective: This study procured two compounds, Debilon and Phorbasterone-B, from Rhodophyta to analyze their in silico and in vitro potential against pathogenic bacterial strains and their acute toxicity. Methods: Debilon and Phorbasterone-B were extracted from Rhodophyta by a previously reported method and were further subsequently exploited computationally for their physicochemical properties, prediction of biological activity and molecular docking against bacterial proteins, toxicity, and experimentally for antibacterial potential against pathogenic strains of Vibrio cholera, Salmonella typhi, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa. Results: Docking studies proved that these molecules possess a chemical affinity for the bacterial proteins and can inhibit the growth of these microorganisms, as confirmed by antibacterial assay. Whereas the prediction analysis and toxicity studies showed that the friendliness of these molecules to the human body is enormous. Conclusion: From this study, it has been proved that DN and PB are perfect candidates for inhibiting these bacterial strains.

Background & Objectives: Heterocyclic pyrimidine and pyrazole rings have attracted the interest of medicinal chemists because of their pharmacological potential including antimicrobial activity. Based on molecular hybridization, new chalcones 6a-g and pyrimidines 7a-g based on a pyrazole scaffold were designed. Methods: The synthesis of these compounds involved mild condensation reactions between compound 4 and various aromatic aldehydes in a mixture of ethanol/NaOH (95:5 v/v) to give the corresponding chalcones 6a-g. These chalcones were further reacted with urea in the presence of a base in ethanol to produce the pyrimidine derivatives 7a-g. These new candidates were screened for their in vitro antimicrobial activities and molecular docking studies were evaluated. Results: The antibacterial and antifungal studies of all synthesized compounds against the strains tested showed that compounds 6c, d, and 7c, d exhibited the highest antibacterial and antifungal activities. In addition, the structure-activity relationship and docking studies are discussed. Conclusion: The synthesized compounds 6c, 6d, 7c, and 7d showed the highest antibacterial and antifungal activities against the tested strains.

Objective: The mechanism of Vaccaria segetalis (VS) seeds and Gleditsia sinensis Lam (GS) thorns in the treatment of prostate cancer (PC) was analyzed via network pharmacological analysis methods and molecular docking. Methods: The Traditional Chinese Medicine Systems Pharmacology Database Platform (TCMSP) was used to screen the PC’s effective components and targets; GeneCards and OMIM databases to search for targets related to PC. The intersection target was uploaded to the STRING database to obtain a proteinprotein interaction (PPI) network; and the key targets were screened from the PPI network via R language, CytoNCA, and CytoHubba tools. Gene Ontology (GO) and Kyoto encyclopedia of genes and genome (KEGG) pathway enrichment tools were used to analyze biological processes and molecular docking of key targets via AutoDock Vina software. Results: A total of 13 compounds, 229 nodes, 879 edges, and 20 key targets were obtained through the PPI network. Go and KEGG analysis showed that the intersection targets of VS and GS with PC were mainly involved in regulating cell promotion, cell apoptosis, cell cycle, and reversing epithelialmesenchymal transition (EMT) processing. Molecular docking revealed that the relevant targets of potential PC were characterized with stabilized affinity. Specifically, the targets with better affinity included estrogen receptor 1 (ESR1) with kaempferol, transcription factor p65 (RELA) with fisetin, kaempferol, quercetin, and mitogen-activated protein kinase 1 (MAPK1) with fisetin, and G1/S-specific cyclin-D1 (CCND1) with fisetin, kaempferol, and quercetin. Conclusion: In summary, this study reveals potential molecular therapeutic mechanisms of VS and GS in PC and provides a reference for the wide application of VS and GS in the clinical management of PC.

Aims: In silico Identification of Novel SphK1 Inhibitors. Background: A tumor is one of the major causes of death worldwide; the emergence of new targeted drugs has changed the mode of tumor treatment and opened up the era of targeted therapy. Sphingosine kinase 1 (SphK1) is a strictly conserved lipid checkpoint kinase, mainly located in the cytosol, and is overexpressed and enhances the development and progression of various type of tumors, such as melanoma, esophageal, gastric, and colon cancers. SphK1, consisting of 384 amino acid residues, has two domains: C-terminal (CTD) and N-terminal (NTD). SphK1 phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), which exists in high concentration in both the plasma and the lymph of cancer patients. S1P has 5 receptors (S1PRs) and controls 5 signal pathways, Ras/Raf/MEK1/2, PI3K/Akt, G-protein/PLC/PKC, Rho/Rock/NF-ĸB and PTEN; they are all related to cell growth, proliferation, differentiation, apoptosis, migration, and stress fiber formation. The sphK1/S1P signal pathway influences tumor cells' growth, proliferation, survival and angiogenesis, and SphK1 inhibitors can decrease Treg cell recruitment at tumor location. In T cells, SphK1/S1P signal way activates NF-ĸB and induces proliferator-activated receptor γ (PPARγ) transcription, which in turn regulates lipolysis in T cells. SphK1 can induce T cell failure through excessive S1P in extracellular vesicles of the tumor microenvironment. SphK1 inhibitors block S1P generation and inhibit cell growth, proliferation, differentiation, apoptosis, migration, and stress fiber formation, leading to increased CD8⁺T cells and decreased Treg cells in the tumor microenvironment. S1P also upregulates the expression of programmed cell death 1 ligand 1(PD-L1) through Early 2-factor transcription factor 1 (E2F1). Objective: The discovery of better Sphk1 inhibitors by pharmacophore model, ADMET, molecular docking, MM/GBSA, and MD simulation. Methods: Here, SphK1 pharmacophore was created; first, it was used for virtual screening, ADMET properties of screened-out molecules were predicted, and the obtained molecules were performed molecular docking and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) calculation, then molecular dynamics (MD) simulation was performed, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) were calculated. Results: Compounds 1, 2, and 3 were obtained through screening, and the binding energy of 1, 2, and 3 were better than that of the existing corresponding target inhibitors. Conclusion: The overexpression of Sphk1 is closely related to the occurrence, development, migration and drug resistance of tumors and has a good prospect of drug development. Given the important role of SphK1 inhibitors in treating tumors and the shortcomings of clinical application of SphK1 inhibitors, small molecule targeting inhibition SphK1 was screened to overcome the low efficiency. Firstly, establishing a pharmacophore model for virtual screening, and then ADMET prediction, sixty-seven molecules were selected. And then, molecular docking and MM/GBSA calculation obtain three compounds with lower Glide Score. In addition, they both have lower binding energy than PF-543. The docking result shows that Asp167, Asp264, and Thr282 of SphK1 with ligand more easily form H-bonds interaction. Next, in molecular dynamics simulation, compounds 1, 2, and 3 can stably bind with SphK1 and have a high activity of inhibiting SphK1, with more research potential. In conclusion, compounds 1, 2, and 3 inhibit SphK1 laying a foundation for further compound synthesis and activity evaluation. Compounds 1, 2 and 3 can stably bind to the receptor protein, which is valuable for further experimental research.