ADME in silico

Previous studies have shown that 2-arylbenzimidazole derivatives have a strong anti-diabetic effect. To further explore this potential, we develop new analogues of the compound using ligand-based drug design and tested their inhibitory and binding properties through QSAR analyses, molecular docking, dynamic simulations and pharmacokinetic studies. By using quantitative structure activity relationship and ligand-based modification, a highly precise predictive model and design of potent compounds was developed from the derivatives of 2-arylbenzimidazoles...

Many people around the world suffer from neurodegenerative diseases associated with cognitive impairment. As life expectancy increases, this number is steadily rising. Therefore, it is extremely important to search for new treatment strategies and to discover new substances with potential neuroprotective and/or cognition-enhancing effects. This study focuses on investigating the potential of astragaloside IV (AIV), a triterpenoid saponin with proven acetylcholinesterase (AChE)-inhibiting activity naturally occurring in the root of Astragalus mongholicus , to attenuate memory impairment...

Lipophilicity is one of the most important properties of compounds required to estimate the absorption, distribution, and transport in biological systems, in addition to solubility, stability, and acid-base nature. It is crucial in predicting the ADME profile of bioactive compounds. The study assessed the usefulness of computational and chromatographic methods (thin-layer chromatography in a reversed-phase system, RP-TLC) for estimating the lipophilicity of 21 newly synthesized compounds belonging to diquinothiazines and quinonaphthiazines...

Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles...

Cancer poses a significant global health challenge and significantly contributes to mortality. NEK7, related to the NIMA protein kinase family, plays a crucial role in spindle assembly and cell division. The dysregulation of NEK7 is closely linked to the onset and progression of various cancers, especially colon and breast cancer, making it a promising target for cancer therapy. Nevertheless, the shortage of high-quality NEK7 inhibitors highlights the need for new therapeutic strategies. In this study, we utilized a multidisciplinary approach, including virtual screening, molecular docking, pharmacokinetics, molecular dynamics simulations (MDs), and MM/PBSA calculations, to evaluate natural compounds as NEK7 inhibitors comprehensively...

Chalcone and triazole scaffolds have demonstrated a crucial role in the advancement of science and technology. Due to their significance, research has proceeded on the design and development of novel benzooxepine connected to 1,2,3-triazolyl chalcone structures. The new chalcone derivatives produced by benzooxepine triazole methyl ketone 2 and different aromatic carbonyl compounds 3 are discussed in this paper. All prepared compounds have well-established structures to a variety of spectral approaches, including mass analysis, 1 H NMR, 13 C NMR, and IR...

Nonclinical studies involve in vitro, in silico, and in vivo experiments to assess the toxicokinetics, toxicology, and safety pharmacology of drugs according to regulatory requirements by a national or international authority. In this review, we summarize the potential effects of various underlying diseases governing the absorption, distribution, metabolism, and excretion (ADME) of drugs to consider the use of animal models of diseases in nonclinical trials. Obesity models showed alterations in hepatic metabolizing enzymes, transporters, and renal pathophysiology, which increase the risk of drug-induced toxicity...

The aims of this work were to evaluate the expression of histamine H3 receptor (H3 R) in triple negative breast cancer (TNBC) samples and to investigate the antitumoral efficacy and safety of the LINS01 series of H3 R antagonists, through in silico, in vitro, and in vivo approaches. Antitumor activity of LINS01009, LINS01010, LINS01022, LINS01023 was assayed in vitro in 4T1 and MDA-MB-231 TNBC cells (0.01-100 μM), and in vivo in 4T1 tumors orthotopically established in BALB/c mice (1 or 20 mg/kg)...

BACKGROUND: Small molecule phytocompounds can potentially ameliorate degenerative changes in cerebral tissues. Thus, the current study aimed to evaluate the neuroprotective efficacy of phytocompounds of methanolic shoots extract of Calligonum polygonoides L. (MSECP) in hypercholesterolemia-associated neurodegenerations. METHODS: Phytochemical screening of the extract was made by LCMS/MS and validated by a repository of the chemical library. The hypercholesterolemia was induced through the intraperitoneal administration of poloxamer-407 with a high-fat diet...

Using structural similarity approach we identified dillapiole, a phenylpropanoid, the main component of Piper aduncum L. and Anethum graveolens L. essential oils as potential PPARγ agonist. Molecular docking revealed that dillapiole binds to the active site of PPARγ, similar to pioglitazone binding. In silico ADME studies showed that dillapiole has high water solubility and GI absorption. Dillapiole was also observed to be partial agonist of PPARγ receptors with EC50 of 43.95 µM...

The catalytic activity of chitosan (Cs) and grafted Cs led to the preparation of terephthalohydrazide Cs Schiff's base hydrogel (TCsSB), which was then investigated as an eco-friendly biocatalyst for synthesizing novel thiazole derivatives. TCsSB exhibited greater surface area and higher thermal stability compared to Cs, making it a promising eco-friendly biocatalyst. We synthesized two novel series of thiazoles via the reaction of 2-(2-oxo-1,2-diphenylethylidene) hydrazine-1-carbothioamide with various hydrazonoyl chlorides and 2-bromo-1-arylethan-1-ones, employing ultrasonic irradiation and using TCsSB as a catalyst...

Herein, we report the synthesis and characterization of novel 1,3,4-oxadiazole derivatives, 2-methoxybenzyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate ( C1 ) 2-methoxybenzyl 5-(2-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate ( C2 ), and methoxybenzyl 5-(3-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate ( C3 ) obtained through desulfurative cyclization reaction. The compound C2 was crystallized, and its crystal structure was elucidated using single-crystal X-ray diffraction technique. The Hirshfeld surface analysis was carried out to analyze, visualize and globally appreciate the weak interactions involved in crystal packing...

Since ancient times, bioactive phytocompounds from different parts of medicinal plants have been used to heal various disease ailments and they are now regarded as a valuable source of disease prevention globally.  Kalanchoe pinnata  is a member of the Crassulaceae family; it has a long history of usage in traditional ayurvedic treatment. Analysis of bioactive compounds for their potential anti-type-2 diabetes mellitus (T2DM) mechanism along with  in-vitro  and  in-silico  approaches was studied in the present research...

OBJECTIVE: The purpose of this study is to comparatively analyze the anticancer properties of Tetrahydrocannabinol (THC), Cannabidiol (CBD), and Tetrahydrocannabivarin (THCV) using In silico tools. METHODS: Using SwissADME and pkCSM, the physicochemical and pharmacokinetics properties of the cannabinoids were evaluated. Protox-II was utilized for the assessment of their cytotoxicity. The chemical-biological interactions of the cannabinoids were also predicted using the Way2Drug Predictive Server which comprises Acute Rat Toxicity, Adver-Pred, CLC-Pred, and Pass Target Prediction...

Lipophilicity, a significant physicochemical parameter of bioactive molecules, along with absorption, distribution, metabolism, excretion parameters and toxicity risk, was investigated for 32 thiazolo[3,2-b][1,2,4]triazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives with anti-inflammatory potential. The experimental lipophilicity study was carried out by reversed-phase thin-layer chromatography in a binary isopropanol-water mobile phase, and the obtained results were compared with the theoretical lipophilicity parameters estimated by various computational methods...

The development of effective inhibitors targeting the Kirsten rat sarcoma viral proto-oncogene (KRASG12D ) mutation, a prevalent oncogenic driver in cancer, represents a significant unmet need in precision medicine. In this study, an integrated computational approach combining structure-based virtual screening and molecular dynamics simulation was employed to identify novel noncovalent inhibitors targeting the KRASG12D variant. Through virtual screening of over 1.7 million diverse compounds, potential lead compounds with high binding affinity and specificity were identified using molecular docking and scoring techniques...

In this study, we designed two series of novel anthraquinone-based benzenesulfonamide derivatives and their analogues as potential carbonic anhydrase inhibitors (CAIs) and evaluated their inhibitory activities against off-target human carbonic anhydrase II (hCA II) isoform and tumor-associated human carbonic anhydrase IX (hCA IX) isoform. Most of these compounds exhibited good inhibitory activities against hCA II and IX. The compounds that exhibited the best hCA inhibition were further studied against the MDA-MB-231, MCF-7, and HepG2 cell lines under hypoxic and normoxic conditions...

Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II ( h CA I and h CA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE...

Series of 7-(Trifluoromethyl) substituted indolizine 4a-g was synthesized using the one-pot method. Spectroscopic techniques such as IR, 1 H-NMR, 13 C-NMR, and HRMS were used for the structure confirmation of newly synthesized compounds. These 4a-g compounds were tested for their anti-inflammatory activity. In this study, we identified novel indolizine derivative compounds 4a-g selectively targeting COX-2 enzyme, tumor necrosis factor-α (TNF-α) and, interleukin-6 (IL-6). The in silico docking studies of 4a-g showed that these compounds have a higher affinity for COX-2 enzyme, TNF- α, and IL-6...

The COVID-19 pandemic caused by the SARS-CoV-2 virus, recognized by the World Health Organization (WHO), has led to 164,523,894 confirmed cases and 3,412,032 deaths globally as of May 20, 2021. SARS-CoV-2 encodes crucial proteases for its replication cycle, including the papain-like protease (PLpro), presenting a potential target for developing COVID-19 treatments. Mauritine, a cyclopeptide alkaloid found in the Ziziphus-spina christi plant, exhibits antiviral properties and was investigated for its affinity and toxicity towards PLpro using molecular docking through MGLTools 1...