Drug-likeness Prediction Research Articles

CovalentInDB 2.0: an updated comprehensive database for structure-based and ligand-based covalent inhibitor design and screening.

The rational design of targeted covalent inhibitors (TCIs) has emerged as a powerful strategy in drug discovery, known for its ability to achieve strong binding affinity and prolonged target engagement. However, the development of covalent drugs is often challenged by the need to optimize both covalent warhead and non-covalent interactions, alongside the limitations of existing compound libraries. To address these challenges, we present CovalentInDB 2.0, an updated online database designed to support covalent drug discovery. This updated version includes 8303 inhibitors and 368 targets, supplemented by 3445 newly added cocrystal structures, providing detailed analyses of non-covalent interactions. Furthermore, we have employed an AI-based model to profile the ligandability of 144 864 cysteines across the human proteome. CovalentInDB 2.0 also features the largest covalent virtual screening library with 2 030 192 commercially available compounds and a natural product library with 105 901 molecules, crucial for covalent drug screening and discovery. To enhance the utility of these compounds, we performed structural similarity analysis and drug-likeness predictions. Additionally, a new user data upload feature enables efficient data contribution and continuous updates. CovalentInDB 2.0 is freely accessible at http://cadd.zju.edu.cn/cidb/.

In-silico Study of Molecular Docking and Dynamics Simulations for N-Substituted Thiazolidinones Derived from (R)-Carvone Targeting PPAR-γ Protein: Synthesis and Characterization

In this article, we have selected the monoterpene (R)-carvone combined with thiazolidinone as scaffold. Moreover, this study details the synthesis, characterization, and theoretical analysis of novel (R)-Carvone-thiazolidinone-N-substituted derivatives, sourced from natural (R)-Carvone. The compounds were identified using HRMS, and 1H- and 13C-NMR spectral data. A theoretical analysis provided insights into the stability observed experimentally. The local electronic properties and topological features of two compounds 3 and d were studied using the Multiwfn tool and CrystalExplorer software. Specifically, the electron localization function, localized orbital locator and average local ionization energy were mapped to explore electron distribution, while interaction region indicator was used to analyze intermolecular interactions. An in silico docking study was conducted on the PPAR-γ protein to evaluate the binding affinity and interactions. Furthermore, a 200 ns molecular dynamics simulation was performed to confirm the stability of the compounds within the PPAR-γ protein’s binding site. The results indicated consistent stability for all three compounds under dynamic conditions. Lastly, in silico evaluations of drug-likeness and toxicity prediction showed that all compounds adhere to the criteria of both Lipinski’s Rule of Five and Jorgensen’s Rule of Three, confirming their potential as drug candidates.

Computational and in vitro analyses of the antibacterial effect of the ethanolic extract of Pluchea indica L. leaves.

The most common gram-negative, Escherichia coli, and gram-positive bacteria, Bacillus spp., have evolved different mechanisms that have caused the emergence of multi-drug resistance. As a result, drugs that block the bacterial growth cycle are needed. Here, in silico and in vitro studies were performed to assess compounds in the Pluchea indica leaf extract, a medicinal plant, that can inhibit bacterial proteins. Briefly, P. indica leaves were extracted using ethanol. The crude extract was then subjected to gas chromatography-mass spectrometry for metabolite screening. Molecular docking simulations with rhomboid protease (Rpro) (Protein data bank ID number: 3ZMI from E. coli and filamenting temperature-sensitive mutant Z (FtsZ) protein data bank ID number: 2VAM from Bacillus subtilis were performed. Moreover, the well diffusion method was used to confirm the antibacterial activity of P. indica leaf extract. A total of 10 compounds were identified in the P. indica extract and used for computational analysis. Based on drug-likeness prediction, P. indica compounds may be drug-like molecules. Binding affinity tests indicated that 10,10-Dimethyl-2,6-dimethylenebicyclo(7.2.0)undecan-5.β.-ol and 11,11-Dimethyl-4,8-dimethylenebicyclo(7.2.0)undecan-3-ol had the most negative values. Accordingly, these compounds may be potential ligands that bind to bacterial proteins. The root mean square fluctuation values was <2 Å, indicating stable fluctuation binding for the ligand-protein complex. According to in vitro antibacterial assays, a high concentration (50%) of the P. indica extract markedly inhibited E. coli and B. subtilis, with inhibitory zone diameters of 31.86±1.63 and 21.09±0.09 mm, respectively. Overall, the compounds in the P. indica leaf extract were identified as functional inhibitors of E. coli and B. subtilis proteins via in silico analysis. This may facilitate development of antibacterial agents.

Sulfaquinoxaline-derived Schiff bases: Synthesis, characterization, biological profiling, and computational modeling

Here, six sulfaquinoxaline Schiff bases were synthesized, and various analytical techniques such as FTIR, 1HNMR, and 13CNMR were employed for the characterization. Additionally, in-vitro biological studies were performed, including antibacterial, antifungal, antioxidant, antidiabetic, and anti-inflammatory activities. Computational tools such as molecular docking, DFT, and MD simulations were applied to explore the binding interactions, molecular structure, and chemical reactivity of sulfaquinoxaline SBs. Lastly, in-silico ADMET studies were performed to investigate drug-likeness properties, toxicity, and metabolism of the synthesized SBs. The prepared SBs demonstrated strong antibacterial activity against S. agalactiae and E. coli better than the standard drug, sulfaquinoxaline. The SBs possessed non-significant antioxidant (DPPH assay) and antidiabetic activities (α-amylase and α-glucosidase). All the derivatives depicted moderate anti-inflammatory activity except 6e (IC50 131.95 µg/mL) which presented comparable activity to the standard drug, diclofenac sodium (IC50 127.27 µg/mL). Computational analyses supported the experimental results, especially for compounds 5e and 6e confirming the robust binding affinities and enduring interactions of SBs with the protein target. In-silico drug-likeness analysis and ADMET prediction demonstrated that SBs were drug-like and had a satisfactory ADMET profile.

Exploring Quinazoline Nitro-Derivatives as Potential Antichagasic Agents: Synthesis and In Vitro Evaluation.

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease in humans. The current antichagasic drugs nifurtimox and benznidazole have inconveniences of toxicity; therefore, the search for alternative therapeutic strategies is necessary. The present study reports the synthesis, drug-likeness predictions, and in vitro anti-trypanosome activity of a series of 14 quinazoline 2,4,6-triamine derivatives. All compounds were tested against T. cruzi (epimastigotes and trypomastigotes) and in HFF1 human foreskin fibroblasts. The bioassays showed that compounds 2-4 containing nitrobenzoyl substituents at 6-position of the quinazoline 2,4,6-triamine nucleus were the most potent on its antiprotozoal activity. The effect was observed at 24 h and it was preserved for at least 5 days. Also, compounds 2-4 were not toxic to the human control cells, showing high selectivity index. The quinazoline nitro derivatives have potential use as antichagasic agents.

Novel alloxazine analogues: design, synthesis, and antitumour efficacy enhanced by kinase screening, molecular docking, and ADME studies

This study describes the development of novel alloxazine analogues as potent antitumor agents with enhanced selectivity for tumour cells. Twenty-nine out of 45 newly compounds were investigated in vitro for their growth inhibitory activities, against two human tumour cell lines, namely, the human T-cell acute lymphoblastoid leukaemia cell line (CCRF-HSB-2) and human oral epidermoid carcinoma cell line (KB), and the antitumor agent “Ara-C” was used as a positive reference in this investigation. Compounds 9e and 10J were the highest among their analogues, against both tumour cell lines (CCRF-HSB-2 and KB). Correlation analyses demonstrated a strong relationship between the IC50 values and AutoDock binding free energy or calculated inhibition (Ki ). The study delves into structure–activity relationships (SARs) through advanced modelling tools integrated with structure-based drug design (SBDD) using GOLD 5.2.2, AutoDock 4.2, and Accelrys Discovery Studio 3.5. Physicochemical properties, pharmacokinetics, drug-likeness, and toxicity predictions of the most potent alloxazine derivatives were conducted using ProTox-II and Swiss ADME for effective antitumor agents with improved selectivity.

Experimental and computational profiling of novel bis-Schiff base derivatives bearing α-naphthalene moiety as potential tyrosinase inhibitors

A library of novel bis-Schiff base derivatives (2a-u) of α-naphthalene moiety was successfully synthesized by four step reactions. Following structural elucidation, these products were evaluated for their in vitro tyrosinase inhibitory potential. In the series, nine derivatives (2e, 2r, 2t, 2 g, 2 u, 2p, 2a, 2d, and 2 h) attributed excellent inhibitory activity in the range of IC50 values from 2.3 ± 1.7 to 17.6 ± 0.9 µM superior to the standard drug kojic acid. Similarly, four compounds showed significant activities near to the standard while the remaining eight compounds displayed good to moderate inhibition with IC50 values from 29.3 ± 2.9 to 63.2 ± 1.1 µM. The molecular docking investigations for most active compounds (2e, 2r, 2t, 2 g, 2 u, 2p, 2a, 2d, and 2 h) form high stability in binding site of the tyrosinase active site, than standard kojic acid. Frontier molecular orbitals, such as HOMO and LUMO to show the charge transfer from molecule to biological medium and MEP map to show the chemically reactive zone appropriate for drug action, are calculated using TD-DFT. Besides, the drug-likeness prediction showed that these compounds showed a desirable property, such as high intestinal absorption, large volume of distribution, good BBB penetration, and low toxicity. These bis-Schiff bases have a high oral bioavailability, which can categorized as a unique drug candidate in future.

Interactions and mechanisms of phenolic compounds with human immunodeficiency virus-1 Tat protein

Human immunodeficiency virus remains a serious health threat, with an increase of 24% newly cases globally. Targeting Tat protein is an emerging therapeutic strategy for inhibiting the feedback loop that drives the exponential increase in viral transcription and particle production of the virus. The study aimed to determine the inhibitory potential of phenolic compounds from Ricinus communis L. and Jatropha curcas L., against the Tat C protein using in silico techniques. Phenolic compounds identified from both plants were screened by absorption-distribution-metabolism-excretion (ADME) analysis using drug-likeness prediction. Molecular docking analysis of the compounds with drug-like properties against the receptor and ligand-protein complexes’ analysis and visualization were performed. The results revealed three phenolic compounds with the highest negative binding affinity to the receptor’s active site: ellagic and neochlorogenic acids with - 7.2 kcal/mol and isohemiphloin with -7.3 kcal/mol. The interacting amino acids of the complexes were majorly His13, Lys19, Lys28, Thr64, His65, Gln66, Pro70, Gln72, and Pro73 via non-covalent interactions: hydrogen bonds, hydrophobic, and electrostatic interactions. The identified phenolic compounds provide a core structure that can be candidate for plant-based antiviral drugs development to potentially aiding in the virus’s therapeutic challenge.

Computer-aided discovery of novel SmDHODH inhibitors for schistosomiasis therapy: Ligand-based drug design, molecular docking, molecular dynamic simulations, drug-likeness, and ADMET studies.

Schistosomiasis, also known as bilharzia or snail fever, is a tropical parasitic disease resulting from flatworms of the Schistosoma genus. This often overlooked disease has significant impacts in affected regions, causing enduring morbidity, hindering child development, reducing productivity, and creating economic burdens. Praziquantel (PZQ) is currently the only treatment option for schistosomiasis. Given the potential rise of drug resistance and the limited treatment choices available, there is a need to develop more effective inhibitors for this neglected tropical disease (NTD). In view of this, quantitative structure-activity relationship studies (QSAR), molecular docking, molecular dynamics simulations, drug-likeness, and ADMET predictions were applied to 31 inhibitors of Schistosoma mansoni Dihydroorotate dehydrogenase (SmDHODH). The designed QSAR model demonstrated robust statistical parameters including an R2 of 0.911, R2adj of 0.890, Q2cv of 0.686, R2pred of 0.807, and cR2p of 0.825, confirming its robustness. Compound 26, identified as the most active derivative, emerged as a lead candidate for new potential inhibitors through ligand-based drug design. Subsequently, 12 novel compounds (26A-26L) were designed with enhanced inhibition activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding and hydrophobic interactions, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules (26A and 26L). Furthermore, drug-likeness and ADMET prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for treating schistosomiasis.

Molecular Dynamics Simulation Studies of Beta-Glucogallin and Dihydro Dehydro Coniferyl Alcohol from Syzygium cumini for its Antimicrobial Activity on Staphylococcus aureus.

With the escalating threat of antimicrobial resistance (AMR), discovering novel therapeutic agents against resistant pathogens like Staphylococcus aureus is crucial. This study explores phytochemicals from Syzygium cumini for their potential efficacy against AMR S. aureus infections, elucidating their mechanisms through in silico methods. We investigated 83 compounds from S. cumini, sourced from PubMed, using rigorous docking analysis against the ATP binding domain AgrC of S. aureus with AMdock with Autodock Vina v1.5.2. Drug-likeness predictions were assessed using SwissADME v2023 and Pass online v2.0. Molecular dynamics (MD) simulations identified promising compounds, focusing on stability and interaction dynamics. Beta-Glucogallin (BEG) and Dihydro Dehydro Coniferyl alcohol (DIH) emerged as significant hits. MD simulations with GROMACS v2020.6 revealed stable BEG and DIH complexes with AgrC, forming six hydrogen bonds with six key amino acids (Arg-303, Asp-338, Glu-342, Glu-384, Lys-389, Gly-396), indicating strong and stable bonding. The binding affinities for DIH and BEG are -73.474 ± 11.104 kJ/mol and -6.319 ± 18.823 kJ/mol with 4BXI, respectively. Our findings highlight BEG and DIH as promising candidates against AMR S. aureus infections, showing favourable binding affinities and stable interactions with AgrC. This study underscores the importance of natural products in combating AMR and demonstrates the utility of computational methodologies in drug discovery. Further experimental validation is warranted to fully exploit these phytochemicals' therapeutic potential.

Phytochemical composition, antioxidant activity, and cytotoxicity of the aqueous extracts of Dracaena arborea and Bridelia ferruginea: In vitro and in silico studies

Dracaena arborea (DA) and Bridelia ferruginea (BF) are medicinal plants used in the treatment of various ailments such as diabetes, infertility, and sexual dysfunctions. The aim of this work was to characterize these plants chemically and investigate their antioxidant and cytotoxicity in vitro and in silico. The cytotoxicity was determined in PC3, NIH3T3 and BT474 cells, and through hemolysis using erythrocytes. Furthermore, selected compounds from DA and BF were docked against some oxidative stress (Keap1: Kelch-like ECH-associated protein 1 and GST: glutathione S-transferase) and cytotoxicity (PARP10: poly(ADP-ribose) polymerase family member 10 and p90 RSK: p90 ribosomal S6 kinases) proteins to predict the ligand-protein interaction. We found that the total phenolic and flavonoid content in BF was significantly (p < 0.001) higher than that of DA. 16 and 32 phytocompounds were identified in DA and BF, respectively. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS+) free radical scavenging activity, and cupric and ferric reducing power of BF were significantly (p < 0.05–0.001) higher than those of DA. Moreover, the ability of BF to inhibit lipid peroxidation was higher than that of DA. DA dose-dependently decreased the viability of PC3, NIH3T3, and BT474 cells, while BF tended to feed the cells. Drug-Likeness and toxicity prediction of selected compounds found in DA and BF were within the acceptable standards, according to Lipinski's rule. The majority of compounds found in DA and BF exhibited a strong binding affinity with Keap1, GST, PARP10 and p90 RSK, which supports the in vitro results. For instance, Cis-cyclohexane-1,3-diamine from DA showed a binding affinity of -6.73 kcal/mol and interacted with Keap1 through five conventional hydrogen bonds, while Nrf2 (a Keap1 inhibitor) exhibited a binding affinity of -11.82 kcal/mol and interacted with Keap1 via two conventional hydrogen bonds. 1,3-propanediamine, n-methyl identified in BF exhibited a high stability with Keap1 (-5.95 kcal/mol) due to the presence of 6 conventional hydrogen bonds. Among the compounds identified in DA, the best stable ligand interacting with PARP10 was 2-deoxy-alpha-d-ribopyranose (-7.62 kcal/mol), as it was well-matched in the PARP10 pocket through five conventional hydrogen bonds. In parallel, among the compounds present in BF, 2-[(methylamino)methyl]cyclohexanol showed the best binding affinity with PARP10 (-9.80 kcal/mol), which was higher than that of veliparib (-8.26 kcal/mol), used as a reference inhibitor. In conclusion, BF has the possibility to be exploited in the prevention/treatment of oxidative stress-related diseases, while DA could be a potential anticancer agent. This could justify their ethnomedicinal uses.

Sonochemical synthesis, characterization, and ADMET studiesof Fe (II) and Cu (II) nano-sized complexes of trimethoprim

Nanoparticles exhibit distinct physical and chemical characteristics and are becoming increasingly significant in the production of innovative nanodevices for many applications in physics, biology, biomedicine, and pharmaceuticals. The aim of this research work is to synthesize Fe (II) and Cu (II) nano-sized complexes of trimethoprim (TMP) using the sonication method, characterize them using physical and spectroscopic methods, and carry out ADMET studies on the synthesized complexes. The spectroscopic and physical studies showed a change in colour and an increase in melting point due to coordination. The novel compounds were slightly soluble in water. The XRD tests revealed that the new nanocomplexes were crystalline. The Fe (II) nanocomplexes had a size of 57.56 nm and the Cu (II) nanocomplexes had a size of 69.88 nm. These values were found using Debye-Scherrer’s equation. The FTIR results of the TMP, Fe (II), and Cu (II) nanometal complexes showed a shift of the amino group band from 3317 to 3295 and 3202 cm?1 and the azomethine band from 1633 to 1625 and 1592 cm?1 in the complexes. In the complexes, the proton NMR spectra revealed an upfield shift of the amine proton. The carbon-13 NMR spectra showed that CH2 was involved in coordination with the metal ions. The spectra studies indicated that TMP coordinated with the metal ions through the methylene and amino groups. A trigonal bipyramid structure was proposed for the complexes. The results of the Rule of 5 studies indicated that the test compounds had a good drug-likeness prediction, with only one violation. The ADMET prediction showed that all of the compounds demonstrated improved pharmacokinetic characteristics and adhered to the RO5 requirement. These findings highlight the therapeutic potential of Fe (II) and Cu (II) nano-sized TMP complexes as bioactive compounds that warrant further investigation for pharmaceutical applications.

Exploring novel Apalutamide analogues as potential therapeutics for prostate cancer: design, molecular docking investigations and molecular dynamics simulation.

Introduction: Prostate cancer (PC) ranks as the second most frequent type of cancer in men and is the fourth largest cause of mortality worldwide. Androgenic hormones such as testosterone and dihydrotestosterone are crucial for the development and progression of the prostate gland. Androgenic hormones bind to androgen receptors (AR) and trigger the synthesis of many genes that stimulate the growth of prostate cells, initiating PC growth. Apalutamide (APL) is a non-steroidal antiandrogen drug used to treat PC; however, it also causes a variety of toxicities and resistance during the treatment. Methods: The purpose of this study was to computationally identify new and safer analogues of APL, focusing on improved pharmacokinetic properties and reduced toxicity. Drug likeness (DL) and drug score (DS) were also calculated. Docking studies on the designed analogues were conducted to predict their binding affinities and compare their orientations with the ligands in the original crystal structure. Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite. Results: We generated a total of 1,415 analogues for different groups of APL using the bioisosteric approach. We selected 80 bioisosteres based on pharmacokinetic profiles, DL and DS score predictions, and found that the designed APL bioisosteres were optimal to good compared to APL. Analogues APL19, APL35, APL43, APL76, and APL80, formed hydrogen bonds with protein (PDB ID: 5T8E) which is similar hydrogen bonding to the standard (APL). The MD simulation result confirmed that APL43 and APL80 complexes were stable during the 100nS run. Discussion: The results suggest that the APL analogues, particularly APL43 and APL80, are predicted to be potential antiandrogen drugs for the treatment of prostate cancer.

Acylated glucopyranosides: FTIR, NMR, FMO, MEP, molecular docking, dynamics simulation, ADMET and antimicrobial activity against bacterial and fungal pathogens

Carbohydrates, among the most abundant and widespread biomolecules in nature, play indispensable roles in diverse biological functions and represent a treasure trove of untapped potential for pharmaceutical applications. From this perspective, the present study was designed to explore and evaluate the synthesis and spectral characterization of methyl α-D-glucopyranoside derivatives 2-6 with different aliphatic groups through comprehensive in vitro antimicrobial screening, physicochemical analysis, molecular docking and molecular dynamics analysis, and pharmacokinetic prediction. The unimolar one-step propionylation of methyl α-D-glucopyranoside under controlled conditions furnished 6-O-propionyl derivative 2 and the development of glucoopyranoside-based potential antimicrobial derivatives, which were further converted into four newer 2,3,4-tri-O-glucopyranoside derivatives (3-6) in reasonably good yields. The chemical structures of the newly synthesized analogs were ascertained by analyzing their physicochemical, elemental, FTIR, and NMR spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi indicated the promising antibacterial functionality of these synthesized analogs compared with their antifungal activity. Structure-activity relationship (SAR) analysis indicated that adding lauroyl> stearoyl > palmitoyl groups to the ribose moiety increased the potency against bacterial and fungal strains. In support of this observation, molecular docking experiments were performed on the 3TI6 H1N1 receptor and the 6VMZ H5N1 receptor. Molecular interactions with solvents were investigated in terms of FMO, HOMO-LUMO, and MEP properties. In addition, a 100 ns molecular dynamics simulation process was performed to monitor the behavior of the complex structure formed by the receptor 6VMZ under in silico physiological conditions to examine its stability over time, which revealed a stable conformation and binding pattern in a stimulating environment of methyl α-D-glucopyranoside derivatives. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico.

In silico development of novel angiotensin-converting-enzyme-I inhibitors by Monte Carlo optimization based QSAR modeling, molecular docking studies and ADMET predictions

Within the realm of pharmacological strategies for cardiovascular diseases (CVD) like hypertension, stroke, and heart failure, targeting the angiotensin-converting enzyme I (ACE-I) stands out as a significant treatment approach. This study employs QSAR modeling using Monte Carlo optimization techniques to investigate a range of compounds known for their ACE-I inhibiting properties. The modeling process involved leveraging local molecular graph invariants and SMILES notation as descriptors to develop conformation-independent QSAR models. The dataset was segmented into distinct sets for training, calibration, and testing to ensure model accuracy. Through the application of various statistical analyses, the efficacy, reliability, and predictive capability of the models were evaluated, showcasing promising outcomes. Additionally, molecular fragments derived from SMILES notation descriptors were identified to elucidate the activity changes observed in the compounds. The validation of the QSAR model and designed inhibitors was carried out via molecular docking, aligning well with the QSAR results. To ascertain the drug-worthiness of the designed molecules, their physicochemical properties were computed, aiding in the prediction of ADME parameters, pharmacokinetic attributes, drug-likeness, and medicinal chemistry compatibility.

Chemical and bioprotective studies of Xylopia aethiopica seed extract and molecular docking of doconexent and cryptopinone as the prominent compounds

Fourteen phytochemical compounds were identified in the gas chromatography/mass spectrometry (GC/MS) analysis of the petroleum ether extract of the seeds of Xylopia aethiopica. The compounds comprised of terpenoids (56.027 %), unsaturated fatty acids (30.081 %), alcohol (9.385 %) and saturated fatty acid (4.507 %). The extract showed high antioxidant activity in a dose dependent pattern at a minimum and maximum concentrations of 25 and 400 μg/ml respectively and could be compared with that of ascorbic acid used as a standard antioxidant agent. The antibacterial activity screening of the extract against five pathogenic bacteria organisms indicated that the extract possessed more antibacterial activity than gentamicin used as a standard antibacterial agent. The trend of activity was Klebsiella pneumoniae (gram-negative) &gt; Shigella flexneri (gram-negative) &gt; Staphylococcus epidermidis (gram-positive) &gt; Escherichia coli (gram-negative) &gt; Streptococcus pneumoniae (gram-positive). The presence of high amount of terpenoids in the extract of X. aethiopica could be the reason for the high antioxidant and antibacterial activities shown by the extract and also suggests why the seed extract of the plant is used in herbal medicine for the treatment of diseases and infections. All of the test compounds had negative binding affinities, according to molecular docking modelling, indicating that the compounds had been successfully docked to the receptors. The compounds showed good pharmacokinetic properties, such as high blood-brain barrier absorption, oral bioavailability, and water solubility, in the in-silico ADME and drug-likeness predictions. The findings of this study significantly increase the relevance of these compounds as promising first targets for the treatment of drug resistant bacteria. This may help pharmacologists and other medicinal chemists create and synthesize even more potent drug candidates.

Exploring the Potential of Avenanthramides and their Analogues as α-Glucosidase Inhibitors for Type 2 Diabetes Treatment Utilizing Virtual Screening, Molecular Dynamics, and Drug-likeness Predictions

Exploring the Potential of Avenanthramides and their Analogues as α-Glucosidase Inhibitors for Type 2 Diabetes Treatment Utilizing Virtual Screening, Molecular Dynamics, and Drug-likeness Predictions

Unveiling potent inhibitors for schistosomiasis through ligand-based drug design, molecular docking, molecular dynamics simulations and pharmacokinetics predictions.

Schistosomiasis is a neglected tropical disease which imposes a considerable and enduring impact on affected regions, leading to persistent morbidity, hindering child development, diminishing productivity, and imposing economic burdens. Due to the emergence of drug resistance and limited management options, there is need to develop additional effective inhibitors for schistosomiasis. In view of this, quantitative structure-activity relationship studies, molecular docking, molecular dynamics simulations, drug-likeness and pharmacokinetics predictions were applied to 39 Schistosoma mansoni Thioredoxin Glutathione Reductase (SmTGR) inhibitors. The chosen QSAR model demonstrated robust statistical parameters, including an R2 of 0.798, R2adj of 0.767, Q2cv of 0.681, LOF of 0.930, R2test of 0.776, and cR2p of 0.746, confirming its reliability. The most active derivative (compound 40) was identified as a lead candidate for the development of new potential non-covalent inhibitors through ligand-based design. Subsequently, 12 novel compounds (40a-40l) were designed with enhanced anti-schistosomiasis activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules. Furthermore, drug-likeness and pharmacokinetics prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for the treatment of schistosomiasis.

COMPOSITION OF VOLATILE BIOACTIVE COMPOUNDS OF SEA CUCUMBER (HOLOTHURIA ATRA) EXTRACT AND THEIR BIOACTIVITY AS ANTIVIRALS FOR SARS-COV-2 COVID-19

COVID-19 is a pandemic that has an impact on all aspects of life. This pandemic is caused by the SARS-CoV-2 virus, which has a fast pathogenesis cycle, so alternatives are needed, such as incredibly natural and marine ingredients that can be used as drug candidates. Holothuria atra is an animal candidate that has great potential. This study aims to describe the potential of H. atra as an antiviral candidate for COVID-19 through in silico analysis. The research began with extracts and GC-MS tests to identify the compound content in H. atra. Molecular docking analysis, Lipinski druglikeness, and toxicity predictions were carried out to determine the potential of the compound as an antiviral candidate for COVID-19 through inhibition of RNA-dependent RNA-polymerase protein (RdRp) and human Angiotensin Converting Enzym-2 (hACE2). The research results showed that there were five volatile compounds in the methanol extract of H. atra with one potential compound as a COVID-19 antiviral, namely Cyclohexanone, 2,6-bis((4-methoxyphenyl)methylene)-. Lipinskis druglikeness analysis and toxicity prediction provide support as a COVID-19 antiviral. Further research, such as in vitro and in vivo testing, can be carried out to give an overview of living cells and its activity as an antiviral for COVID-19.

Synthetically Feasible De Novo Molecular Design of Leads Based on a Reinforcement Learning Model: AI-Assisted Discovery of an Anti-IBD Lead Targeting CXCR4.

Artificial intelligence (AI) de novo molecular generation provides leads with novel structures for drug discovery. However, the target affinity and synthesizability of the generated molecules present critical challenges for the successful application of AI technology. Therefore, we developed an advanced reinforcement learning model to bridge the gap between the theory of de novo molecular generation and the practical aspects of drug discovery. This model utilizes chemical reaction templates and commercially available building blocks as a starting point and employs forward reaction prediction to generate molecules, while real-time docking and drug-likeness predictions are conducted to ensure synthesizability and drug-likeness. We applied this model to design active molecules targeting the inflammation-related receptor CXCR4 and successfully prepared them according to the AI-proposed synthetic routes. Several molecules exhibited potent anti-CXCR4 and anti-inflammatory activity in subsequent in vitro and in vivo assays. The top-performing compound XVI alleviated symptoms related to inflammatory bowel disease and showed reasonable pharmacokinetic properties.