Drug-likeness Rules Research Articles

In Silico Protein-Ligand Interaction Study of Selected Phytochemicals Against Monoamine Oxidase-B

Parkinson’s disease (PD) is a progressive neurodegenerative disease associated with the death of dopaminergic neurons in the substantia nigra pars compacta. Monoamine oxidase B (MAO-B) inhibitors lessen the degree of PD but still present various side effects. Natural products such as morin, piceatannol, resveratrol, and gallic acid are vital phytochemicals from plants with numerous health benefits. This in silico study aimed to identify potent natural MAO-B inhibitors that could serve as better alternatives to the known MAO-B inhibitors (rasagiline and selegiline). The crystal structure of MAO-B (PDB ID: 2C65) was retrieved from the Protein Data Bank (RSCB) and prepared for molecular docking via Discovery Studio 2020 software. Molecular docking between MAO-B and morin, piceatannol, resveratrol, gallic acid, rasagiline, and selegiline utilised the PyRx software. The Discovery Studio 2020 software was used for visualization. The SwissADME server was used to study the physiochemical properties (Lipinski rule of five), pharma-cokinetic parameters, and absorption, distribution, metabolism, elimination, and toxicity (ADMET) profiles of morin. Comparing results with binding affinity indicated that morin (-10.0 kcal/mol) has a superior potency against 2C65 than piceatannol (-9.0 kcal/mol), resveratrol (-807 kcal/mol), dopamine (-6.4 kcal/mol), gallic acid (-6.3 kcal/mol), rasagiline (-8.0 kcal/mol), and selegiline (-7.4 kcal/mol). Drug candidates comply with all five of Lipinski’s drug-likeness rules with appropriate ADMET properties. Overall, the molecular docking results suggest that morin may be considered a suitable therapeutic candidate for PD treatment.

Bioassay-guided identification of potential Alzheimer’s disease therapeutic agents from Kaempferol-Enriched fraction of Aframomum melegueta seeds using in vitro and chemoinformatics approaches

Alzheimer's disease (AD) has become a major public health concern and the fifth major cause of death among the aging population globally. In this study, the total phenols and flavonoids contents (TPC and TFC) and in vitro antioxidant actions of the methanol extract and the various fractions of Aframomum melegueta were evaluated using 2,2-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, nitric oxide scavenging activity (NO), lipid peroxidation (TBARS) activity and ferric reducing power assay (FRAP). Furthermore, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of the two most potent fractions were investigated, and the phytochemicals identified in the ethyl acetate fraction, which had the best antioxidant and cholinesterase inhibitory effects were subjected to chemoinformatics studies. The extract and its fraction had high amounts of TPC and TFC. The ethyl acetate fraction exerted the best DPPH, NO, TBARS, and FRAP inhibition with IC50 values of 5.06, 6.58, 2.12, and 88.73 µg/mL, respectively. Interestingly, n-hexane and ethyl acetate fractions inhibited AChE (IC5016.83 and 11.67 µg/mL) and BuChE (IC50 7.54 and 5.21 µg/mL) enzymatic activities more than the standard inhibitor, rivastigmine which had 11.99 and 11.40 µg/mL IC50 values, respectively. A total of 18 compounds were identified in ethyl acetate fraction, and kaempferol was the major component, with 40.01 µg/g (30%). More strikingly, the top-scoring compounds (catechin, and kaempferol) exhibited good binding affinity, and interacted favorably with amino acids residues around and within the active sites of AChE and BuChE and also obeyed drug-likeness rules, and did not show a tendency towards toxicity when placed side by side with rivastigmine which is immunogenic. Thus, A. melegueta seeds contain safe bioactive chemicals, which could be a veritable remedy for managing Alzheimer's and other neurodegenerative diseases.

Green Synthesis and Acetylcholinesterase Inhibition of Coumarin-1,2,4-Triazole Hybrids

Abstract: The pursuit of biologically active compounds has led many researchers to synthesize different heterocyclic hybrids with prominent activity. Both coumarin and 1,2,4-triazole are very potent scaffolds whose hybrids have improved biological activities. : This study synthesized twenty-one new coumarin-1,2,4-triazole hybrids in a one-step reaction using choline chloride : urea deep eutectic solvent. The green approach to this synthesis has led to shorter reaction times, higher yields, and purity of final compounds. : The title compounds were characterized and screened for drug-likeness parameters to evaluate their viability as potential drug candidates and for their in vitro acetylcholinesterase inhibitory activity. All tested compounds complied with the drug-likeness rules. However, they exhibited only weak to moderate inhibitory activity against acetylcholinesterase. : Molecular docking analysis revealed that title compounds mostly bind to the peripheral anionic region of the acetylcholinesterase active site, therefore hindering, but not completely obstructing, substrate from entering the enzyme catalytic site.

In silico elucidation of potential drug targets against oxygenase domain of Human eNOS Dysfunction.

Nitric Oxide (NO) signaling pathway plays a vital role in various physiological and pathophysiological processes including vasodilation, neurogenesis, inflammation, translation and protein regulation. NO signaling pathway is associated with various diseases such as cardiovascular diseases, vision impairment, hypertension and Alzheimer's disease. Human Endothelial Nitric Oxide Synthase (eNOS) bound with calcium regulatory protein (calmodulin (CaM)) to produce NO which initiates cGMP pathway. The current study employs to screen the novel compounds against human eNOS independent of calcium regulatory protein (CaM). The current effort emphasized that the deficiency of CaM leads to dysfunction of cGMP signaling pathway. In this work, a hybrid approach of high-throughput virtual screening and comparative molecular docking studies followed by molecular dynamic simulation analyses were applied. The screening of top ranked two novel compounds against eNOS were reported that showed effective binding affinity, retrieved through the DrugBank and ZINC database libraries. Comparative molecular docking analyses revealed that Val-104, Phe-105, Gln-247, Arg-250, Ala-266, Trp-330, Tyr-331, Pro-334, Ala-335, Val-336, Tyr-357, Met-358, Thr-360, Glu-361, Ile-362, Arg-365, Asn-366, Asp-369, Arg-372, Trp-447 and Tyr-475 are potent residues for interactional studies. High-throughput virtual screening approach coupled with molecular dynamic simulation and drug likeness rules depicted that ZINC59677432 and DB00456 are potent compounds to target eNOS. In conclusion, the proposed compounds are potent against eNOS based on extensive in silico analyses. Overall, the findings of this study may be helpful to design therapeutic targets against eNOS.

An insight into the mechanisms of action of selected bioactive compounds against epigenetic targets of prostate cancer: implications on histones modifications.

Prostate cancer is a leading cause of morbidity and mortality among men globally. In this study, we employed an in silico approach to predict the possible mechanisms of action of selected novel compounds reported against prostate cancer epigenetic targets and their derivatives, exhausting through ADMET profiling, drug-likeness, and molecular docking analyses. The selected compounds: sulforaphane, silibinin, 3, 3'-diindolylmethane (DIM), and genistein largely conformed to ADMET and drug-likeness rules including Lipinski's. Docking studies revealed strong binding energy of sulforaphane with HDAC6 (- 4.2kcal/ mol), DIM versus HDAC2 (- 5.2kcal/mol), genistein versus HDAC6 (- 4.1kcal/mol), and silibinin against HDAC1 (- 7.0kcal/mol) coupled with improved binding affinities and biochemical stabilities after derivatization. Findings from this study may provide insight into the potential epigenetic reprogramming mechanisms of these compounds against prostate cancer and could pave the way toward more success in prostate cancer phytotherapy.

Facing Antitubercular Resistance: Identification of Potential Direct Inhibitors Targeting InhA Enzyme and Generation of 3D-pharmacophore Model by in silico Approach.

The enoyl-acyl carrier protein reductase (InhA) is one of the important key enzymes employed in mycolic acids biosynthesis pathway and an important component of mycobacterial cell walls. This enzyme has also been identified as major target of isoniazid drug, except that isoniazid needs to be activated first by the catalase peroxidase (KatG) protein to form the isonicotinoyl-NAD (INH-NAD) adduct that inhibits the action of InhA enzyme. However, this activation becomes more difficult and unreachable with the problem of mutation-related resistance caused mainly by acquired mutations in KatG and InhA protein. Our main interest in this study is to identify direct InhA inhibitors using computer-aided drug design. Computer-aided drug design was used to solve this problem by applying three different approaches including mutation impact modelling, virtual screening and 3D-pharmacophore search. A total of 15 mutations were collected from the literature, then a 3D model was generated for each of them and their impact was predicted. Of the 15 mutations, 10 were found to be deleterious and have a direct effect on flexibility, stability and SASA of the protein. In virtual screening, from 1,000 similar INH-NAD analogues obtained by the similarity search method, 823 compounds passed toxicity filter and drug likeness rules, which were then docked to the wild-type of InhA protein. Subsequently, 34 compounds with binding energy score better than that of INH-NAD were selected and docked against the 10 generated mutated models of InhA. Only three leads showed a lower binding affinity better than the reference. The 3D-pharmacophore model approach was used to identify the common features between those three compounds by generating a pharmacophoric map. The result of this study may pave the way to develop more potent mutant-specific inhibitors to overcome this resistance.

In Silico Screening of Phytochemicals Targeting SmdCD of Streptococcus mutans using Molecular Docking Approach

Introduction: Dental caries is a chronic infectious disease caused by bacteria forming a biofilm formation on the tooth surface. Drug-resistant bacteria Streptococcus mutans (S. mutans) pose a vital public health issue. To overcome this, the development of effective drugs with a novel mechanism of action is very important. Drug repurposing is considered a viable alternative approach to overcome the above issue. In the present study, we have attempted to select unique and traditional source used as in traditional medicine. To continue this effort, in this study we used phytochemical of selected to find an effective cure for dental caries. Materials and methods: Inhibition of S. mutans deoxycytidylate deaminases (SmdCDs) is a promising drug development strategy against S. mutans, responsible for biofilm formation. Since no effective drugs are available against S. mutans, we conducted a virtual screening of phytochemicals to find novel compounds against this bacterium. Hence, we created a library of 871 phytochemicals from 13 plants with reported antimicrobial activity. The phytochemical library was subjected to virtual screening against the SmdCD target. Results and discussion: Traditionally, many cultures use chewing sticks for oral hygiene maintenance. In the present work, out of 871 phytochemicals, 211 phytochemicals showed the most druggable substance with zero violation from any of the drug-likeness rules. Further, the binding energy indicates the affinity of adhesion of protein structure docked with 2 hit potential herbal compounds of which Cyclocurcumin and Androsta-1,4,6-triene-3,17-dione showed the best docking with SmdCD. Conclusions: Based on the binding energy score, we suggest that hit compounds can be used for dental caries and further could be developed as an organic mouthwash. HIGHLIGHTS Streptococcus mutans is common in the human oral cavity and contributes significantly to tooth decay mutans deoxycytidylate deaminases (SmdCDs) are responsible for biofilm formation causing drug resistance SmdCDs can be used to develop effective drug against mutans, responsible for biofilm formation Screening phytochemicals may result potential compounds which can be used to develop new drugs against mutans GRAPHICAL ABSTRACT

New flavone-based arylamides as potential V600E-BRAF inhibitors: Molecular docking, DFT, and pharmacokinetic properties

ObjectivesThe V600E-BRAF protein kinase is an attractive and essential therapeutic target in melanoma and other tumors. However, because of its resistance to the known inhibitors and side effects of some identified inhibitors, new potent inhibitors need to be identified. MethodsIn the present work, in silico strategies such as the molecular docking simulation, DFT (Density-Functional-Theory) computations, and pharmacokinetic evaluation were used to determine potential V600E-BRAF inhibitors from a set of 31 synthesized novel flavone-based arylamides. ResultsThe docking result demonstrated that four compounds (10, 11, 28, and 31) had acceptable docking scores (MolDock score of −167.523 kcal mol−1, −158.168 kcal mol−1, −160.581 kcal mol−1,−162.302 kcal mol−1, and a Rerank score of −124.365, −129.365, −135.878 and −117.081, respectively) appeared as most active and potent V600E-BRAF inhibitors that topped vemurafenib (−158.139 and −118.607 kcal mol−1). The appearance of H-bonds and hydrophobic interactions with essential residues for V600E-BRAF proved the high stability of these complexes. The energy for the frontier molecular orbitals such as HOMO, LUMO, energy gap, and other reactivity parameters was computed using DFT. The frontier molecular-orbital surfaces and electrostatic potentials (EPs) were investigated to demonstrate the charge-density distributions that might be linked to anticancer activity. Similarly, the chosen compounds revealed superior pharmacological properties according to the drug-likeness rules (bioavailability) and pharmacokinetic properties. ConclusionThe chosen compounds were recognized as potent V600E-BRAF inhibitors with superior pharmacokinetic properties and could be promising cancer drug candidates.

Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential V600E-BRAF kinaseinhibitors

ObjectivesV600E-BRAF kinase is an essential therapeutic target in melanoma and other types of tumors. Because of its resistance to known inhibitors and the adverse effects of some identified inhibitors, investigation of new potent inhibitors is necessary. MethodsIn the present work, in silico strategies such as molecular docking simulation, pharmacokinetic evaluation, and density functional theory (DFT) computations were used to identify potential V600E-BRAF inhibitors from a set of 72 anticancer compounds in the PubChem database. ResultsFive top-ranked molecules (12, 15, 30, 31, and 35) with excellent docking scores (MolDock score ≥90 kcal mol−1, Rerank score ≥60 kcal mol−1) were selected. Several potential binding interactions were discovered between the molecules and V600E-BRAF. The formation of H-bonds and hydrophobic interactions with essential residues of V600E-BRAF suggested the high stability of these complexes. The selected compounds had excellent pharmacological properties according to the drug likeness rules (bioavailability) and pharmacokinetic properties. Similarly, the energy for the frontier molecular orbitals, such as the HOMO, LUMO, energy gap, and other reactivity parameters, was computed with DFT. The frontier molecular orbital surfaces and electrostatic potentials were investigated to demonstrate the charge-density distributions potentially associated with anticancer activity. ConclusionThe identified compounds were found to be potent hit compounds for V600E-BRAF inhibition with superior pharmacokinetic properties; therefore, they may be promising cancer drug candidates.

A Schiff Base with Polymorphic Structure (Z′ = 2): Investigations with Computational Techniques and in Silico Predictions

In this study, we report a newly synthesized Schiff base molecule named (E)-N-(2-chloropyridin-3-yl)-1-(5-nitro-2-(piperidin-1-yl)phenyl)methanimine. We also report its structural, chemical, surface, and electronic properties, potential targets, drug-likeness, ADME and toxicity profile, and docking studies for the main protease (Mpro) of SARS-CoV-2. The scope of this study includes the topological and electronic properties, intermolecular interactions, physicochemical and pharmacokinetic properties, metabolic pathways, toxicity endpoints, blood–brain barrier (BBB) permeability, and intestinal absorption activities. We performed the above analyses using bioinformatics/chemoinformatics tools and computational techniques. The topic crystal/compound (TC) contains two crystallographically independent molecules in the asymmetric unit (Z′ = 2). TC is open to attack by electrophilic and nucleophilic species and is a soft, chemically reactive, kinetically unstable material. There are no deviations from the known drug-likeness rules. BBB penetration and GI absorption of TC are possible. The docking values of the complex Mpro/TC and Mpro/native ligand N3 were calculated to be −8.10 and −7.11 kcal/mol, respectively. Therefore, we can say that TC is a potential Mpro inhibitor and can be investigated for further laboratory studies.

Exploring Scutellaria baicalensis bioactives as EGFR tyrosine kinase inhibitors: Cheminformatics and molecular docking studies

The Epidermal Growth Factor Receptor (EGFR) pathway plays a pivotal role in cancer progression, making it a prime target for anticancer drug development. Scutellaria baicalensis, a traditional Chinese medicinal herb, harbors bioactive compounds with promising pharmacological properties, including potential EGFR tyrosine kinase inhibition. In this study, we employed a comprehensive approach merging cheminformatics and molecular docking techniques to investigate the glioblastoma multiforme inhibitory potentials of the bioactive compounds from the plant, with a focus against EGFR. Our findings revealed significant binding affinities ranging from −9.010 to −6.427 kcal/mol and intricate molecular interactions between compounds from S. baicalensis and the EGFR. Notably, Ganhuangenin, 5,7,2′,5′-tetrahydroxyflavone, (2R)-2-(2,6-dihydroxyphenyl)-3,4-dihydro-2H-chromene-5,7-diol, and tenaxin I showed particularly high binding affinities, with scores ranging from −9.010 to −8.649 kcal/mol. These compounds even outperformed erlotinib, a standard ligand with a score of −8.539 kcal/mol. Importantly, they interacted with key amino acid residues (Met769, Glu738, and Thr766) through hydrogen bonding. These interactions were driven by specific structural features, including aromatic rings, hydrogen bond donors and acceptors, and hydrophobic interactions and the reliability of these results was further confirmed through induced-fit docking, reinforcing the potential inhibitory effects of these compounds on the flexible protein. Additionally, all of the top-scoring compounds from S. baicalensis adhered to established drug-likeness rules, including Lipinski's criteria, Ghose's rules, Veber's guidelines, and Egan's rules. However, it's worth noting that scutellarin had some violations in these rules. Remarkably, none of the identified compounds were likely to cause hepatotoxicity, mutagenicity, or cytotoxicity, suggesting that they could be considered as safe candidates for anti-cancer agents. This multidisciplinary investigation bridges traditional herbal knowledge and modern drug discovery, offering insights into the potential of S. baicalensis bioactive compounds as novel EGFR-targeting agents. The results underscore the value of chemoinformatics and molecular docking studies in exploring natural compounds for cancer therapy, paving the way for further research in the field.

Virtual Screening, Synthesis, and Biological Evaluation of Some Carbohydrazide Derivatives as Potential DPP-IV Inhibitors

Dipeptidyl peptidase-4 (DPP-IV) inhibitors are known as safe and well-tolerated antidiabetic medicine. Therefore, the aim of the present work was to synthesize some carbohydrazide derivatives (1a-5d) as DPP-IV inhibitors. In addition, this work involves simulations using molecular docking, ADMET analysis, and Lipinski and Veber's guidelines. Wet-lab synthesis was used to make derivatives that met all requirements, and then FTIR, NMR, and mass spectrometry were used to confirm the structures and perform biological assays. In this context, in vitro enzymatic and in vivo antidiabetic activity evaluations were carried out. None of the molecules had broken the majority of the drug-likeness rules. Furthermore, these molecules were put through additional screening using molecular docking. In molecular docking experiments (PDB ID: 2P8S), many molecules displayed more potent interactions than native ligands, exhibiting more hydrogen bonds, especially those with chloro- or fluoro substitutions. Our findings indicated that compounds 5b and 4c have IC50 values of 28.13 and 34.94 µM, respectively, under in vitro enzymatic assays. On the 21st day of administration to animals, compound 5b exhibited a significant reduction in serum blood glucose level (157.33 ± 5.75 mg/dL) compared with the diabetic control (Sitagliptin), which showed 280.00 ± 13.29 mg/dL. The antihyperglycemic activity showed that the synthesized compounds have good hypoglycemic potential in fasting blood glucose in the type 2 diabetes animal model (T2DM). Taken all together, our findings indicate that the synthesized compounds exhibit excellent hypoglycemic potential and could be used as leads in developing novel antidiabetic agents.

In silico Screening of Potential Compounds from Medicinal Plants by Targeting Streptococcus mutans Deoxycytidylate Deaminase

Dental caries is the chronic infectious disease caused by bacteria to from a biofilm formation on the tooth surface of man. Drug-resistant Streptococcus mutans (S. mutans) poses a vital public health issue. To overcome this, the development of effective drugs with novel mechanism of action is requisite. Drug repurposing is considered a viable alternative approach to overcome the above issue. In the present study, we have attempted to selected unique and traditional source use as in traditional medicine. Traditionally, many cultures use chewing sticks for oral hygiene maintenance. When properly used, these chewing sticks are found to be efficient due to the combined effect of mechanical cleaning, enhanced salivation and the antimicrobial action of leached out plant. Inibition of the S. mutans deoxycytidylate deaminases (SmdCDs) is the most promising drug development strategy against the S. mutans, responsible for the biofilm formation. In the present work, out of 871 phytochemicals 211 phytochemicals were showed the most druggable substance with zero violation from any of druglikeness rule. Further, the binding energy indicates the affinity of the adhesion of protein structure docked with the 2 hit potential herbal compounds of which Cyclocurcumin and Androsta-1,4,6-triene-3,17-dione showed best docking with the SmdCD.

Computer-aided analysis for identification of novel analogues of ketoprofen based on molecular docking, ADMET, drug-likeness and DFT studies for the treatment of inflammation

Computer-based drug design is increasingly used in strategies for discovering new molecules for therapeutic purposes. The targeted drug is ketoprofen (KTP), which belongs to the family of non-steroidal anti-inflammatory drugs, which are widely used for the treatment of pain, fever, inflammation and certain types of cancers. In an attempt to rationalize the search for 72 new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines molecular docking towards COX-2 receptor (5F1A), ADMET pharmacokinetic parameters, drug-likeness rules and molecular electrostatic potential (MEP). It was found that six of the compounds analyzed satisfy with the associated values to physico-chemical properties as key evaluation parameters for the drug-likeness and demonstrate a hydrophobic character which makes their solubility in aqueous media difficult and easy in lipids. All the compounds presented good ADMET profile and they showed an interaction with the amino acids responsible for anti-inflammatory activity of the COX-2 isoenzyme. The calculation of the MEP of the six analogues reveals new preferential sites involving the formation of new bonds. Consequently, this result allowed us to understand the origin of the potential increase in the anti-inflammatory activity of the candidates. Finally, it was obtained that six compounds have a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug ketoprofen, suggesting that these compounds could become a powerful candidate in the inhibition of the COX-2 enzyme. Communicated by Ramaswamy H. Sarma

Screening, Docking, and Molecular Dynamics Study of Natural Compounds as an Anti-HER2 for the Management of Breast Cancer.

Breast cancer (BC) is one of the most frequent types of cancer that affect women. Human epidermal growth factor receptor-2 (HER2) is responsible for 20% of all BC cases. The use of anti-HER2 natural compounds in the cure of BC that is HER2-positive patients has resulted in significant increases in survival in both early and advanced stages. The findings of in-silico research support the use of ligands as possible HER2 inhibitors, and molecules with high free energy of binding may have considerable anti-BC action, making them candidates for future drug development. The inhibitory activity of selected ligands like ZINC43069427 and ZINC95918662 against HER2 was found to be -11.0 and -8.50 kcal/mol, respectively. The amino acid residues Leu726, Val734, Ala751, Lys753, Thr798, Gly804, Arg849, Leu852, Thr862, and Asp863 were found in common interaction as compared to the control compound Lapatinib. Molecular dynamics study calculations of these selected potent inhibitors were conducted and found to be stable over the 50 ns simulation time in terms of root mean square deviation (RMSD), root-mean square fluctuation (RMSF), radius of gyration (Rg), and solvent accessible surface area (SASA). In addition, there are several parameters such as absorption, distribution, metabolism, and excretion toxicity (ADMET), physicochemical, and drug-likeness that were checked and found in good range to be potential lead-like molecules. Several drug-likeness rules like Lipinski, Ghose, Veber, Egan, and Muegge were checked and found to be positive for these rules. Based on these calculations and different parameters, these top two selected natural compounds can be used as potential candidates for anti-HER2 for the management of BC.

Cytotoxic Potential of Alternaria tenuissima AUMC14342 Mycoendophyte Extract: A Study Combined with LC-MS/MS Metabolic Profiling and Molecular Docking Simulation.

Breast, cervical, and ovarian cancers are among the most serious cancers and the main causes of mortality in females worldwide, necessitating urgent efforts to find newer sources of safe anticancer drugs. The present study aimed to evaluate the anticancer potency of mycoendophytic Alternaria tenuissima AUMC14342 ethyl acetate extract on HeLa (cervical cancer), SKOV-3 (ovarian cancer), and MCF-7 (breast adenocarcinoma) cell lines. The extract showed potent effect on MCF-7 cells with an IC50 value of 55.53 μg/mL. Cell cycle distribution analysis of treated MCF-7 cells revealed a cell cycle arrest at the S phase with a significant increase in the cell population (25.53%). When compared to control cells, no significant signs of necrotic or apoptotic cell death were observed. LC-MS/MS analysis of Alternaria tenuissima extract afforded the identification of 20 secondary metabolites, including 7-dehydrobrefeldin A, which exhibited the highest interaction score (−8.0156 kcal/mol) in molecular docking analysis against human aromatase. Regarding ADME pharmacokinetics and drug-likeness properties, 7-dehydrobrefeldin A, 4’-epialtenuene, and atransfusarin had good GIT absorption and water solubility without any violation of drug-likeness rules. These findings support the anticancer activity of bioactive metabolites derived from endophytic fungi and provide drug scaffolds and substitute sources for the future development of safe chemotherapy.

In Silico Drug Repurposing of 9H-Thioxanthene Based FDA-Approved Drugs as Potent Chemotherapeutics Targeting VEGFR-2 and COX-2

The approach of using existing drugs initially developed for one disease to treat other indications has found success across medical fields. This article emphasizes the drug repurposing of 9H-thioxanthene based on FDA-approved drugs for anticancer agents precisely targeting VEGFR-2 and COX-2. The investigated 9H-thioxanthene drugs 1-4 were analyzed for Lipinski's drug-likeness rule and ideal ADME parameters. The results show that all calculated physicochemical descriptors and pharmacokinetic properties are within the expected range. 9H-thioxanthene drugs 1-4 were subjected to molecular docking to determine their molecular interactions at the active sites of VEGFR-2 and COX-2. The molecular docking study revealed that all four 9H-thioxanthene drugs 1-4 were able to target VEGFR-2 and COX-2. In the future, these findings will be greatly favorable in augmenting the utility of the development of the investigated drugs 1-4 for cancer therapeutics specifically targeting VEGFR-2 and COX-2.

Design, synthesis, spectroscopic characterization, in vitro tyrosinase inhibition, antioxidant evaluation, in silico and kinetic studies of substituted indole-carbohydrazides

In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC50 values in the range of 0.070 to > 100 μM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC50 = 0.070 μM), 8f (R = 4-OH, IC50 = 0.072 μM), and 19e (IC50 = 0.19 μM) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 μM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction.

Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50 parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50 values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible BrPQ5 interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of BrPQ5 was assessed, and IC50 values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of BrPQ5 on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that BrPQ5 caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, BrPQ5 did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.

Computational discovery of small drug-like compounds as potential inhibitors of PD-1/PD-L1 interactions

The programmed cell death ligand protein 1 (PD-L1) is a strong immunosuppressive molecule that inactivates tumor-specific T cells by binding to the programmed cell death- 1 protein (PD-1). Cancer immunotherapy based on the monoclonal antibodies targeting the PD-1/PD-L1 pathway has demonstrated therapeutic responses without precedent over a wide range of cancers. However, the antibody-based immunotherapies have several limitations such as high production cost or the induction of severe immune-related adverse effects. Small-molecule inhibitors of the PD-1/PD-L1 pathway are a promising alternative or complementary therapeutic to antibodies. Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In the present study a pharmacophore model was generated based on previously developed compounds and their atomistic structures with the PD-L1 dimer. Structure-based affinity-based virtual screening of small-molecule inhibitors of the PD-1/PD-L1 pathway according to the pharmacophore model followed by a screening in terms of drug-likeness resulted in ten hit compounds of high affinity towards the PD-L1 dimer and the satisfaction to all of the drug-likeness rules. Molecular dynamics (MD) simulations showed that nine of ten compounds formed stable complexes with the PD-L1 dimer as evidenced by the analysis of MD trajectories. Molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) calculation revealed very low binding energies (<-46 kcal/mol) for the interactions of these ligands with the PD-L1 dimer, suggesting that identified compounds may serve as good scaffolds for the design of novel agents of antitumor immunotherapy able to target the PD-1/PD-L1 interaction Communicated by Ramaswamy H. Sarma