GI Absorption Research Articles

New Sulfonate Ester-Linked Fluorinated Hydrazone Derivatives as Multitarget Carbonic Anhydrase and Cholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, Molecular Docking and ADME Analysis.

In this study, some new hydrazone derivatives (2a-g) was designed, synthesized for first time, and evaluated as multitarget inhibitors of AChE, BChE, hCA I and hCA II. The chemical structures of new hybrids were confirmed by elemental analysis and some spectroscopic techniques. All tested compounds showed low nanomolar inhibition with IC50 values of in the range of 30.4-264.0 nM against hCA I, 23.2-251.6 nM against hCA II, 12.1-114.3 nM against AChE, and 76.4-134.0 nM against BChE. These compounds inhibited hCA I and AChE more than acetazolamide (AZA) and neostigmine. Among them, compounds 2c and 2e, which have a linear structure, were determined to be the most active inhibitor candidates against these selected enzymes. Molecular docking studies were carried out on the compounds (2a--g), revealing their binding interactions with the active site of AChE, BChE, hCA I and hCA II thus supporting the experimental findings. Additionally, in silico absorption, distribution, metabolism, and excretion (ADME) prediction studies of the obtained compounds (2a--g) with in silico approaches were carried out to determine their solubility, whether they have the potential to cross the blood-brain barrier (BBB), values such as GI absorption and drug likeness principles.

12475 Revisiting Myxedema Coma

Abstract Disclosure: M.H. Islam: None. D.R. Jimenez Corado: None. S. Siddiqui: None. M.F. Aquino Camey: None. S. Yeasmin: None. Background: Myxedema coma is a rare and life-threatening complication of hypothyroidism.Although it is rare in the era of better diagnostics and treatment modalities, its life-threatening nature mandates its timely recognition and better understanding. Case:81-year-old female with a history of hypothyroidism (unclear medication compliance) and alcohol use disorder was admitted due to alcohol withdrawal and treated with benzodiazepines. A few days prior to the presentation, she was found to have worsening confusion, unsteady gait, and multiple falls. On presentation, she was hemodynamically stable, tremulous, anxious, and oriented to person only. Blood work was remarkable for mild transaminitis. CT scan of the head revealed sequelae of microvascular disease. The day after admission, she was noted to be lethargic, and benzodiazepines were held. Later, she became hypothermic, hypotensive, bradycardic, and hyponatremic. Further investigation was pursued, revealing a TSH of 55 (normal 0.27 to 4.2 mlU/L), free T4 of <0.10 ng/dL (normal 0.8-1.7 ng/dL), free T3 of <1.0 pg/mL (normal 2.2-4 pg/mL), and cortisol of 10.7 ug/dL. Due to concerns of myxedema coma, she was started on stress dose steroids and IV levothyroxine. She was transferred to the ICU as her mental status continued to deteriorate; she underwent endotracheal intubation and received additional doses of IV levothyroxine and liothyronine. After a few days, her clinical condition and her cortisol, free T4, and free T3 levels improved; she was extubated and later discharged with an adjusted levothyroxine dose. Conclusion: It is of absolute importance to keep myxedema coma as a differential diagnosis when evaluating encephalopathic elderly patients, especially those with a history of thyroid disorders.There is a paucity of evidence to suggest a clear benefit of combining levothyroxine-liothyronine over levothyroxine alone. Treating initially with intravenous levothyroxine over oral is beneficial, as GI absorption and bioavailability are likely variable and unpredictable. In this case, oral liothyronine was used with IV levothyroxine to speed up clinical and biochemical recovery.Adrenal insufficiency often coexists with hypothyroidism, with considerable overlap in clinical features like hypotension, hypoglycemia, and hyponatremia. Administration of levothyroxine before steroids can lead to a rapid increase in metabolic rate and subsequent depletion of the existing reserves. Considering this, it can be said with fair confidence that patients need prior or concomitant stress doses of corticosteroids on an emergent basis. Later, biochemical testing can be done to evaluate the functioning of the hypothalamic-pituitary-adrenal axis and then adjust steroid doses accordingly. Presentation: 6/1/2024

Drug-like screening, molecular docking, molecular dynamics simulations, and binding free energies on the interaction of pyrazole derivatives as inhibitors of lysosomal storage disorders and anticancer activity

Lysosomal membrane proteins (LAMPs) are a primary target for treating tumors because of their essential role in the cancer life cycle. In this study, some computational approaches, including drug-like screening, molecular docking, and molecular dynamics (MD) simulation studies coupled with the binding free energy, have been conducted to explore the putative binding modes of pyrazole derivatives as inhibitors of lysosomal storage disorders. Certain pyrazole derivatives outperformed typical medications in molecular docking experiments against the LAMPs receptor; among other substances, molecules CID 44555488 and 45,487,645 were deemed ideal. Additionally, these ligands (CID 44555488 and 45,487,645) were projected to be orally accessible in humans after successfully passing five separate drug-likeness criteria. In the end, it was anticipated that these ligands, CID 44555488 and 45,487,645, would have minimal human toxicity and good ADMET properties, particularly in terms of GI absorption and the lack of P-gp interaction. Compounds CID 44555488 and 45,487,645 with high predicted binding affinities were subjected to further molecular dynamics simulations based on the molecular docking data, and their potential binding mechanisms were investigated. The study's description of the structure-based drug design approach will be very helpful in the creation of novel inhibitors with excellent selectivity and potency.

Molecular Docking, Pharmacophore Modeling, and ADMET Prediction of Novel Heterocyclic Leads as Glucokinase Activators.

A pivotal impetus has driven the development of numerous small molecules aiming to improve therapeutic strategies for type 2 diabetes. Glucokinase (GK) activation has been offered a new realm of therapeutic antidiabetic activity with novel heter-ocyclic derivatives. In the context of antidiabetic drug design, GK is an interesting and newly validated target. A key enzyme needed for blood glucose homeostasis is Glucokinase, which is dysfunctional in individuals with type 2 diabetes. Heterocyclic derivatives are utilized in this innovative approach to activate GK enzymes as medicinal agents that will significantly improve type 2 diabetes management. To address type 2 diabetes, as well as minimize unwanted side effects, this research endeavor aimed to develop activators of glucokinase. A rigorous scrutiny was conducted of the Maybridge online repository, which houses a formidable collection of 53,000 lead compounds. A collection of 125 compounds that contain the thiazolidinedione core was selected from this extensive collection. The struc-tures were generated using ChemDraw 2D, stabilized conformation with ChemBioDraw Ul-tra, and docked using Auto Dock Vina 1.5.6 in this methodology. In addition, log P was pre-dicted online using the Swiss ADME algorithm. The PKCSM software was used to predict the toxicity of the leading compounds. The highest binding affinity was found for AS72 and AS108 to GK receptors. GI absorption and excretion of these compounds were efficient due to Lipinski's Rule of Five compliance. When compared with the standard drugs Dorzagliatin (GKA) and MRK (co-crys-tallized ligand), these substances demonstrated a notable lack of AMES toxicity, skin sensiti-zation, and hepatotoxicity. In recent studies, lead molecules that possess enhanced pharmacokinetic profiles, increased binding affinity, and lower toxicity were developed to act as glucokinase activators.

Structural activity of synthesized pyrimidine-thiophene and pyrimidine-thiadiazole conjugates as anticancer agents

New pyrimidine linked thiophene conjugates 5a-d and thiadiazole conjugates 7a-d through a carboxamide bridge were synthesized and characterized by the spectral data (IR, NMR and mass). Exploration of the isolated conjugates’ characteristics using DFT methodology revealed that they had angular configurations with distinctive outline of the FMO’s belonging to the thienyl- and thiadiazolyl-pyrimidine classes. In accordance, the FMO’s energy values of these analogues disclosed reduced energy gap (ΔEH-L=3.66–3.86 eV) than the parent 4 (4.49 eV) and may be arranged as: 7c < 7d < 5c < 5d < 5a < 5b < 7b < 7a < 4. Meanwhile, the cytotoxic effectiveness of the synthesized conjugates was assessed against different cancer cell lines using IC50 values in comparison to 5-Fu, drug reference. The data showed that the acrylamide derivative 4 exhibited the most potent cytotoxicity against MCF-7 and PC3 (IC50 6.11 ± 0.10 and 7.19 ± 0.04 μM, respectively). Moreover, the carbonic anhydrases inhibitory effect on hCA IX and hCA IIX have been evaluated, using acetazolamide (as standard), showing greater impact on hCA IX compared to hCA IIX. Molecular docking has been applied to investigate the nature of the binding interactions with the target amino acid residues, and it disclosed that the pyrimidine-thiophene conjugates 5d and 5c had the highest binding scores. Finally, the SwissADME pharmacokinetic properties of synthesized conjugates indicated that the acrylamide compound 4 exhibited acceptable pharmacokinetic manners, such GI absorption, solubility, no BBB permeation, and slight CYP450 inhibition, implying a promising therapeutic candidate.

Some heterocycles connected to substituted piperazine by 1,3,4-oxadiazole linker: Design, synthesis, anticholinesterase and antioxidant activity

AD is a multifactorial neurodegenerative disease that has caused morbidity and mortality on a global scale. Currently, there are only a few drugs used in the treatment of AD. Although many compounds that aim at new targets have reached clinical trials, none have been approved. However, discovering efficient drugs for AD treatment is one of the biggest challenges for pharmaceutical research and requires strong support. In this paper, we aim to design a series of indole, benzothiophene, and thiophene bearing 1,3,4-oxadiazole linker to the piperazine basic center and evaluate for their antioxidant and inhibitory activity against both cholinesterase enzymes. Among the compounds, 6a, 7b, and 8b exhibited moderate cationic radical scavenging activities with IC50 values ranging from 20.39 to 30.10 μM. The inhibitory activity results revealed that compounds 5c (IC50 for AChE = 53.91 μM and for BChE = 55.81 μM) and 6c (IC50 for AChE = 54.42 μM and BChE = 45.82 μM) bearing 2-fluorophenyl piperazine moiety showed both AChE and BChE inhibition with moderate IC50 values. To explore the binding properties of the target compounds into the active site of the enzyme, a molecular docking study was carried out using MOE software. The docking study showed that compound 6c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE/BChE and formed important interactions with key residues. Moreover, theoretical physicochemical properties of the best active compound 6c were calculated by the SwissADME web service. It obeyed Lipinski's rule of five and had high GI absorption (gastrointestinal absorption) and good permeating to the blood-brain barrier (BBB). The compound 6c can be considered a promising compound and provides us directions for further research of anti-AD agent development.

Role of interaction mode of phenanthrene derivatives as selective PDE5 inhibitors using molecular dynamics simulations and quantum chemical calculations.

Phosphodiesterase type 5 (PDE5) inhibitors play a crucial role in blocking PDE5 to improve erectile dysfunction (ED). However, most PDE5 drugs revealed side effects including the loss of vision due to the PDE6 inhibition. Phenanthrene derivatives isolated from E. macrobulbon were previously reported as PDE5 inhibitors. Two phenanthrene derivatives (cpds 1-2) revealed better inhibition to PDE5 than PDE6 and cpd 1 is more selective to PDE5 than cpd 2. To elucidate why the phenanthrene derivatives could inhibit PDE5 and PDE6, their binding modes were investigated using molecular dynamics simulations and quantum chemical calculations, as compared to the PDE5 drugs. From the results, all four drugs and phenanthrene derivatives revealed similar π-π interactions to Phe820 in PDE5. Additional H-bond interaction to Gln817 in PDE5 resulted in better PDE5 inhibition of vardenafil and tadalafil. Moreover, cpds 1-2 were able to form the H-bond interaction with Asp764 in PDE5. In the case of the PDE6, the loss of π-π interaction to Phe776 and H-bond interaction to Gln773 indicated the important points for losing the PDE6 inhibition. In conclusion, to develop the new potent PDE5 inhibitors, not only the important interaction with PDE5 but also the interaction with PDE6 should be considered. In phenanthrene derivatives, the middle ring was significant to form π-π interactions to Phe820 in PDE5 and hydroxyl substituent was also the key part to form the H-bond interaction with Asp764 in PDE5. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated the stability of the system. The bioavailability, drug-likeness, and pharmacokinetics of phenanthrene derivatives were also predicted. These derivatives revealed good drug-likeness and GI absorption. The obtained results showed that phenanthrene derivatives could be interesting for the development of PDE5 inhibitors in the future.

Drug Design, In Silico-Profiling of New Pyrrole Derivatives: Promising Anticancer Agents Against Acute Myeloid Leukemia

Molecular docking simulation and synthesis of five compounds of N2, N4-bis (2-(4-substituted phenyl)-4-oxothiazolidin-3-yl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxamide was carried out to evaluate their theoretical binding affinities, targeting acute myeloid leukemia (AML). The chemical structure of the molecules was accurately drawn using ChemDraw Professional 19.1 software. The designed compounds were evaluated for their selectivity towards FLT3's ATP pocket (PDB ID:6JQR) in comparison with the reference ligand (Gilteritinib) by using GOLD suite from the Cambridge Crystallographic Data Centre (CCDC) software (Version 2021.2.0). All the designed compounds exhibited good binding energies with the receptor active pocket and had promising activity. Compounds 2E and 3E showed the highest PLP Fitness (83.30, 80.86 respectively) and it is higher than that of Gilteritinib (71.91). In-silico ADME and drug-likeness studies were performed by using the Swiss ADME server. The results showed that most of the designed compounds expected to be absorbed from the GIT. Compounds 2B-E have high expected GI absorption. All the investigated compounds have no predicted BBB penetration. Additionally, compounds 2A, 2C, 2D, and 3A are not a substrate to P-gps which may indicate a lower expected incidence of resistance by cancer cells in vitro studies. Finally, all of the investigated compounds are not considered to inhibit CYP1A2 enzyme, except for compounds 2A and 3D.

Molecular modeling and cytotoxic activity of newly synthesized benzothiazole-thiazole conjugates

In the dynamic area of drug development, researchers have been urged to uncover and test novel compounds with better effectiveness and fewer side effects in order to find more effective cancer treatments. In this comprehensive study, the synthesis and anticancer efficacy of new benzothiazole-thiazole have been displayed. Initially, a series of benzothiazole-thiazole conjugates 5a-c, 7a-b, and 8 were carefully designed and synthesized from the versatile 6-acetyl-2-phenylsulfonamidobenzothiazole (2), following the guidelines of rational design principles. The DFT/B3LYP approach showed that the synthesized hybrids had a non-planar configuration, where the benzene-sulfonamide group was oriented almost perpendicularly. The tested derivatives exhibited close HOMO-LUMO energies leading to small energy gaps (ΔEH-L = 1.54–2.97 eV). Additionally, the inhibitory effects of the newly synthesized conjugates were tested on four cancer cell lines, including HepG2, HCT-116, MCF-7, and WI38. Conjugates 5a and 8 had strong inhibitory effects on the HCT-116 and MCF-7 cell lines. Additionally, the synthesized conjugates showed inhibitory action against CAIX and CAXII, where conjugate 8 also effectively inhibited both isoforms, as well as, conjugate 5a. Molecular docking analysis was performed to study the binding affinities and interactions of the newly synthesized benzothiazole-thiazole conjugates with the target PDB: 5fl4 protein. Moreover, the ADME outlines of the inspected conjugates were displayed, and conjugates 2 and 6 showed suitable characteristics for GI absorption and minor violations of Lipinski’s rules; thus, they are promising lead compounds.

Rutaecarpine-inspired scaffold-hopping strategy and Ullmann cross-coupling based synthetic approach: Identification of pyridopyrimidinone-indole based novel anticancer chemotypes

Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure–function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with ‘N’-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N’-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7–15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells’ migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.

Natural products can be potential inhibitors of metalloproteinase II from Bacteroides fragilis to intervene colorectal cancer

Bacteroides fragilis, a gram negative and obligate anaerobe bacterium, is a member of normal gut microbiota and facilitates many essential roles being performed in human body in normal circumstances specifically in Gastrointestinal or GI tract. Sometimes, due to genetics, epigenetics, and environmental factors, Bacteroides fragilis and their protein(s) start interacting with intestinal epithelium thus damaging the lining leading to colorectal cancers (CRC). To identify these protein(s), we incorporated a novel subtractive proteomics approach in the study. Metalloproteinase II (MPII), a Bacteroides fragilis toxin (bft), was investigated for its virulence and unique pathways to demonstrate its specificity and uniqueness in pathogenicity followed by molecular docking against a set of small drug-like natural molecules to discover potential inhibitors against the toxin. All these identified inhibitor-like molecules were analyzed for their ADMET calculations and detailed physiochemical properties to predict their druggability, GI absorption, blood brain barrier and skin permeation, and others. Resultantly, a total of ten compounds with the least binding energies were obtained and were subjected to protein-compound interaction analysis. Interaction analysis revealed the most common ligand-interacting residues in MPII are His 345, Glu 346, His 339, Gly 310, Tyr 341, Pro 340, Asp 187, Phe 309, Lys 307, Ile 185, Thr 308, and Pro 184. Therefore, top three compounds complexed with MPII having best binding energies were selected in order to analyze their trajectories. RMSD, RMSF, Rg and MMPBSA analysis revealed that all compounds showed good binding and keeping the complex stable and compact throughout the simulation time in addition to all properties and qualities of being a potential inhibitor against MPII.

A Scoping Review on Recent Progress on Purpurin and its Derivatives

Background: Purpurin is being used as a red dye for many decades. But recently, due to its pharmacological properties, purpurin and its derivatives have attracted a lot of researchers for the treatment of various ailments, such as cancer, Alzheimer’s disease, depression, etc. Objectives: The objective of this study is to provide an overview of its pharmacological properties, pharmacokinetic studies, synthesis, isolation, quality assurance, and patent studies. Method: A systemic scoping review was undertaken. Three databases (Pubmed, Scopus, and Google Scholar) and patent websites were searched using relevant words (e.g., purpurin, purpurin derivatives, anticancer, toxicity, etc.). All outcomes for studies that met the inclusion criteria were included in the review. Extracted data were accumulated using tables, figures, and accompanying narrative descriptive summaries. The review was reported using the preferred reporting items for scoping review (PRISMAScR) guidelines. Sixty-eight studies and eighty-six patents met the inclusion criteria, mostly preclinical (in vitro, in vivo, and in silico) studies performed in rats, mice, dogs, and zebrafish, followed by one clinical trial study. Results: The potent antioxidant nature of purpurin is the main reason behind its vast pharmacological properties. It acts by decreasing mitochondrial stress and by acting on the endoplasmic reticulum. It also crosses the BBB barrier, has high GI absorption, and follows the Lipinski rule, which makes it a good drug for various neurodegenerative disorders. It inhibits various CYP-450, CYP 1A2, and CYP 3A4 enzymes, which are responsible for causing mutations. It gets photosensitized by UV light and causes ROSdependent apoptosis in cancer cells. Conclusion: This scoping review highlights purpurin and its derivatives as highly prized moieties in the treatment of various neurological conditions and cancer. The unique nature of purpurin is responsible for its pharmacological properties, which are due to the presence of hydroxyl and keto groups at specific positions. It gets photosensitized by UV and laser light and acts as an anticancer drug. But the lack of robust evaluation in clinical studies is another major concern. Purpurin can be seen in the prescription in the future, although a lot of work still needs to be done.

In silico investigation of cannabinoids from Cannabis sativa leaves as a potential anticancer drug to inhibit MAPK-ERK signaling pathway and EMT induction

Genes related to MAPK-ERK signaling pathways, and epithelial-mesenchymal transition induction is evolutionarily conserved and has crucial roles in the regulation of important cellular processes, including cell proliferation. In this study, six cannabinoids from Cannabis sativa were docked with MAPK-ERK signaling pathways to identify their possible binding interactions. The results showed that all the cannabinoids have good binding affinities with the target proteins. The best binding affinities were MEK- tetrahydrocannabinol (– 8.8 kcal/mol) and P13k-cannabinol (– 8.5 kcal/mol). The root mean square deviation was calculated and used two alternative variants (rmsd/ub and rmsd/lb) and the values of rmsd/lb fluctuated 8.6–2.0 Å and for rmsd/ub from 1.0 to 2.0 Å that suggests the cannabinoids and protein complex are accurate and cannot destroy on binding. The study analyzed the pharmacokinetic and drug-likeness properties of six cannabinoids from C. sativa leaves using the SwissADME web tool. Lipinski's rule of five was used to predict drug-likeness and showed that all compounds have not violated it and the total polar surface area of cannabinoids was also according to Lipinski's rule that is benchmarked of anticancer drugs. Cannabinoids are meet the requirements of leadlikeness and synthetic accessibility values showed they can be synthesized. The molecular weight, XLOGP3, solubility (log S), and flexibility (FLEX) are according to the bioavailability radar. The bioavailability score and consensus Log Po/w fall within the acceptable range for the suitable drug. Pharmacokinetics parameters showed that cannabinoids cannot cross the blood–brain barrier, have high GI absorption as well as cannabinoids are substrates of (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4) but no substrate of P-glycoprotein. Based on these findings, the study suggests that cannabinoids are suitable drugs that could be used as effective inhibitors for target proteins involved in cancer pathways. Among the six cannabinoids, cannabinol and tetrahydrocannabinol exerted maximum binding affinities with proteins of MAPK-ERK signaling pathways, and their pharmacokinetics and drug-likeness-related profiles suggest that these cannabinoids could be superlative inhibitors in cancer treatment. Further in vitro, in vivo, and clinical studies are needed to explore their potential in cancer treatment.

Docking study of ferulic acid derivates on FGFR1, ADME prediction, and QSPR analysis

Background: FGFR-1 is an angiogenic receptor that plays a huge role in the cancer growth pathway. Angiogenesis inhibitory drugs released have significant side effects. Therefore, research into discovering anti-angiogenic agents to achieve good health and well-being is still necessary. Objective: To design the novel anti-angiogenic candidates from ferulic acid (FA) by docking study on FGFR1, to predict the ADME profile, and to find out the structural relationship of their pharmacokinetic properties as QSPR analysis. Method: Autodock Tools performed a docking study. ADME prediction was conducted using SwissADME. The MLR approach determined the QSPR model. Result: The docking results showed that FA-8 and FA-18 had the lowest free energy binding, inhibition constant, and GI absorption. The QSPR analysis obtained the equation model: Log HIA = 0,018 Log P2 + 0,069 Log P + 0,020 CMR + 0,001 Etotal + 1,771 with n = 24, correlation coefficient (r)= 0.621, p-value= 0.046 and F-value= 2.975. Conclusion: Modifying FA on the phenolic moiety replaced by an ester increased the activity and ADME profile. The predicted bioavailability was supported by high Log P, molar refractivity (CMR), and electronic factor (Etotal). It is recommended that lipophilicity be increased to achieve better pharmacokinetic properties.

In silico approaches of gandarusa (Justicia gendarussa Burm. f.) potential for osteoporosis prevention via EGF pathway

Context: On a cellular level, osteoporosis is a metabolic bone disease caused by osteoclastic bone resorption that is not offset by osteoblastic bone synthesis. This increases the risk of fractures by making bones weak and brittle. The selective inactivation of the epidermal growth factor receptor (EGFR) in osteoblast lineage cells demonstrated that EGFR promotes bone formation by increasing the number of mesenchymal progenitors. Active compounds of gandarusa (Justicia gendarussa Burm. f.) are potentially playing crucial roles in EGFR activation. Aims: To evaluate the potential of J. gendarussa for osteoporosis prevention via EGF pathway in silico. Methods: A GC-MS approach was used to screen the active compounds from 70 and 95% methanol extraction, which was continued with molecular docking analysis by PyRx v0.8. The visualization and amino acid interactions were also revealed using Discovery Studio software R17. ADME analysis was performed using the SwissADME webserver to consider whether the best compound could be classified as a drug following Lipinsky rule’s of five. Results: The top five compounds with high binding affinity were selected from a total of 33 active compounds detected. One compound, namely eslicarbazepine, has a -6.7 kcal/mol affinity score and passes the threshold for drugs bioavailability, supported by the data of MW compounds 254.28 kDa, low rotatable bonds 1 bond, hydrogen bond acceptors and donors (2), high GI absorption, and ability to permeant to blood-brain barrier system. Conclusions: This finding added new insight into J. gendarussa extract potential as anti-osteoporosis in humans. Nevertheless, in vitro and in vivo experiments are necessary to confirm the potential.

5-Oxo-dihydropyranopyran derivatives as anti-proliferative agents; synthesis, biological evaluation, molecular docking, MD simulation, DFT, and in-silico pharmacokinetic studies

A series of ethyl 2-amino-7-methyl-5-oxo-4-phenyl-4,5-dihydropyrano[4,3-b]pyran-3-carboxylate derivatives (4a-j) bearing different substitutions on the C4-phenyl ring was synthesized. The anti-proliferative activity of all the synthesized compounds was assessed against two human cancer-cell lines, including SW-480 and MCF-7, by using MTT method. Derivatives 4g, 4i, and 4j, possessing 4-NO2, 4-Cl, and 3,4,5-(OCH3)3 substitutions, were found to be the most potent compounds against both cell lines. The obtained IC50 values for 4g, 4i, and 4j were 34.6, 35.9, and 38.6 μM against SW-480 cells and 42.6, 34.2, and 26.6 μM against MCF-7 cells, respectively. Evaluation of the free radical scavenging potential of the compounds against DPPH radicals showed the highest result for compound 4j with an EC50 value of 580 μM. Molecular docking studies revealed the compounds were well accommodated within the binding site of cyclin-dependent kinase-2 (CDK2) with binding energies comparable to those of DTQ (the co-crystallized inhibitor) and BMS-265246 (a well-known CDK2 inhibitor). Molecular dynamics simulation studies confirmed the interactions and stability of the 4g-CDK2 complex. All derivatives, except 4g, were predicted to comply with the drug-likeness rules. Compound 4j may be proposed as an anti-cancer lead candidate for further studies due to the promising findings from in-silico pharmacokinetic studies, such as high GI absorption, not being a P-gp substrate, and being a P-gp inhibitor. Density functional theory (DFT) analysis was performed at the B3LYP/6–311++G (d,p) level of theory to examine the reactivity or stability descriptors of 4d, 4g, 4i, and 4j derivatives. The highest value of energy gap between HOMO and LUMO and thermochemical parameters were obtained for 4i and 4j.

In silico Exploration of Pharmacological and Molecular Descriptor Properties of Salacinol and Its Related Analogues

Salacinol and its related analogues have been known for their potent α-glucosidase inhibitor activity and making them interesting candidates for a new type of anti-diabetic agent. Therefore, it is essential to investigate the physicochemical properties, pharmacological parameters, and toxicity profile of these anti-diabetic agents. In this study, a comprehensive in-silico approach was used to explore the absorption, distribution, metabolism, excretion, and toxicity profiles of salacinol and its related analogues. In addition, to gain a better knowledge of structural and electrical characteristics, global and local reactivity descriptors, and molecular electrostatic potential were calculated and discussed by using DFT at the B3LYP/6–311++G (d, p) level of theory. The results explored that all the studied compounds have low GI absorption and are substrates for P-glycoprotein. None of the compounds can cross the BBB, and none of the compounds are inhibitors of cytochrome P450 isoenzymes. We also found that all compounds have various potential to interact with a wide range of biological targets, including GPCRs, enzymes, ion channels, kinases, and nuclear receptors. Additionally, all compounds have low toxicity and are unlikely to cause any major health hazards in terms of hepatotoxicity, mutagenicity, cardiotoxicity, cytotoxicity, and immunotoxicity. The molecular electrostatic potential map shows that the negative potential sites are in electronegative oxygen atoms, while the positive potential sites are around the hydrogen atoms. The present study concludes that salacinol and its analogues might be a promising safe and effective candidate for the development of therapeutic drugs derived from natural sources. However, some of their properties should be considered in the context of drug development and tissue protection strategies.

3,5-Disubstituted-thiazolidine-2,4-dione hybrids as antidiabetic agents: Design, synthesis, in-vitro and In vivo evaluation

Diabetes is one of the fastest-growing metabolic disorders, nearly doubling the number of patients each year. There are different treatment approaches available for the management of diabetes, which lacks due to their side effects. The inhibition of enzymes involved in the metabolism of complex polysaccharides to monosaccharides has proven beneficial in patients with type 2 diabetes mellitus. Two enzymes, α-amylase and α-glucosidase, have emerged as potential drug targets and are widely explored for drug development against type 2 diabetes mellitus. In this context, thiazolidine-2,4-diones (TZDs) have emerged as potential drug candidates for developing newer molecules against α-amylase and α-glucosidase. Nineteen TZD-hybrids were synthesized and evaluated in vitro α-amylase and α-glucosidase inhibitory activity. The compounds 7i, 7k, and 7p have emerged as the best dual inhibitors with IC50 of 10.33 ± 0.11–20.94 ± 0.76 μM and 10.19 ± 0.25–24.07 ± 1.56 μM against α-glucosidase and α-amylase, respectively. The derivatives had good anti-oxidant activity, displaying IC50 = 14.95 ± 0.65–23.27 ± 0.99 μM. The compounds 7k and 7p showed the best inhibition of reactive oxygen species in the PNAC-1 cells. The molecules exhibit good binding within the active site of α-amylase (PDB id: 1B2Y) and α-glucosidase (PDB id: 3W37), displaying binding energies of −7.5 to −10.7 kcal/mol and −7.4 to −10.3 kcal/mol, respectively. Further, the compounds were nontoxic (LD50 = 500–1311 mg/kg) and possessed good GI absorption. The compounds 7i, 7k, and 7p were evaluated in vivo antidiabetic activity in an STZ-induced diabetic model in Wistar rats. The compound 7p emerged as the best compound in the in vivo studies; however, the activity was lesser than that of the standard drug pioglitazone.

In silico and in vitro prediction of new synthesized N-heterocyclic compounds as anti-SARS-CoV-2

Computer-aided drug design has been employed to get the medicinal effects against Corona virus from different pyridine derivatives after synthesizing the new compounds. Additionally, various computational studies are also employed between the newly prepared pyridine derivatives and three controls against three proteins (6Y2E, 6M71 and 6M3M). Different methods were employed to synthesize new pyridine derivatives according to the literature using different reaction mediums. MTT was performed for cytotoxicity study and IC50 for inhibitory concentration. Additionally, in-silico studies including DFT, molecular docking, molecular dynamics, MMPBSA, ADME, pharmacokinetics and Lipinski rules were evaluated. The chemical structures of all new compounds were elucidated based on spectroscopic investigation. A molecular docking study demonstrated that compounds 5, 11, and 12 have the best binders of the SARS-CoV-2 main protease enzyme, with energy scores of − 7.5 kcal/mol, − 7.2 kcal/mol, and − 7.9 kcal/mol, respectively. The net binding energy values of the 11-Mpro, 12-Mpro, and 5-Mpro complexes revealed their highly stable nature in terms of both intermolecular interactions and docked conformation across the simulation time. ADME properties, besides the pharmacokinetics and Lipinski rules, showed that all seven newly synthesized compounds follow Lipinski rules with high GI absorption. The In Vitro antiviral study against SARS-CoV-2 using MTT methods confirms that compound 5 has more potential and is safer than other tested compounds. The study shows that the newly synthesized pyridine derivatives have medicinal properties against SARS-CoV-2 without violating Lipinski rules. Compounds 5, 11, and 12, particularly compound 5, may serve as promising potential candidate for COVID-19.

System Pharmacological Approach to Investigate and Validate Multitargeted and Therapeutic Effect of Furocoumarins of Apium graveolens L. for Treatment of Kidney Disease.

System pharmacological approaches play important roles in drug discovery and development and in biomolecular exploration to investigate the multitarget therapeutic effects of phytochemicals for the treatment of acute and chronic ailments. The aim of the study was to apply a system pharmacological approach to investigate the multitarget therapeutic effects of furocoumarins of Apium graveolens L. for the treatment of kidney disease. Several furocoumarins of Apium graveolens were screened from online databases. Network biology and poly-pharmacology analyses were performed to investigate the multitarget therapeutic effect of furocoumarins. The potential metabolites that showed significant interactions with various genes were selected for in silico docking analysis with CASP-3 and SOD proteins. In silico ADME analysis was also performed to investigate the pharmacokinetic behavior of targeted furocoumarins. Out of thirteen furocoumarins selected for analysis, six showed partial or significant interaction with SOD and CASP-3 proteins. These metabolites may alleviate kidney dysfunction by reducing oxidative and inflammatory stress, regulating apoptosis, slowing down the progression of diabetic nephropathy, and reducing hypertension and glomerular vascular rigidity. In silico docking analysis revealed bergapten as a potential therapeutic agent for kidney disease treatment. In silico docking analysis showed anglicine, imperatorin, and sphondin exhibited strong interaction with CASP-3 and SOD with binding energy -6.5, -7.2, -6.5 and -6.8, -6.2 -5.7 kcal/mol, respectively. These components exhibited greater conventional hydrogen bonding with CASP-3 and SOD than other furocoumarins. Furthermore, in silico ADME analysis of metabolites showed that all furocoumarins have a highly lipophilic nature, good skin permeability, and GI absorption, as well as good blood-brain permeability (BBB). Furocoumarins reduce kidney dysfunction and associated pathophysiological complications via the reduction of glomerular vascular rigidity, diabetic nephropathy, and oxidative and inflammatory stress. However, further biomolecular and clinical examinations are necessary to validate and enhance the credibility of present findings.