Pharmacophore Query Research Articles

In Silico Exploration of Molecular Mechanisms for Inhibiting Inflammatory Responses by 3Н-Thiazolo[4,5-b]pyridin-2-one Derivatives.

Combined in silico strategy for molecular mechanisms exploration of a series 3H-thiazolo[4,5-b]pyridin-2-ones exhibiting strong anti-exudative action through QSAR analysis, molecular docking and pharmacophore modelling is reported. GA-ML technique was used for QSAR models generation with 2D autocorrelation descriptors. One- and two-parameter regressions revealed that certain structural patterns or heteroatoms contribute mutually to the anti-exudative activity potentiation. Possible action mechanisms were discovered through flexible docking simulations with cyclooxygenase pathway enzymes (COX-1, COX-2, mPGES-1). Docking results indicated the possibility of stable complexes formation with the effective docking scores and proper orientation of ligands within the enzymes active sites. Pharmacophore modelling was carried out using protein-ligand interaction fingerprints methodology. Two- and three-centre 3D pharmacophore queries were constructed. Their analysis indicated the functionality of bicyclic thiazolopyridine scaffold proved by the steric placement of heteroatoms in the corresponding pharmacophore centres.

Computational exploration of novel ROCK2 inhibitors for cardiovascular disease management; insights from high-throughput virtual screening, molecular docking, DFT and MD simulation.

Cardiovascular disorders are the world's major cause of death nowadays. To treat cardiovascular diseases especially coronary artery diseases and hypertension, researchers found potential ROCK2 (Rho-associated coiled-coil-containing protein kinase 2) target due to its substantial role in NO-cGMP and RhoA/ROCK pathway. Available drugs for ROCK2 are less effective and some of them depict side effects. Therefore, a set of novel compounds were screened that can potentially inhibit the activity of ROCK2 and help to treat cardiovascular diseases by employing In-silico techniques. In this study, we undertook ligand based virtual screening of 50 million compound's library, to that purpose shape and features (contain functional groups) based pharmacophore query was modelled and validated by Area Under Curve graph (AUC). 2000 best hits were screened for Lipinski's rule of 5 compliance. Subsequently, these selected compounds were docked into the binding site of ROCK2 to gain insights into the interactions between hit compounds and the target protein. Based on binding affinity and RMSD scores, a final cohort of 15 compounds were chosen which were further refined by pharmacokinetics, ADMET and bioactivity scores. 2 potential hits were screened using density functional theory, revealing remarkable biological and chemical activity. Potential inhibitors (F847-0007 and 9543495) underwent rigorous examination through MD Simulations and MMGBSA analysis, elucidating their stability and strong binding affinities. Results of current study unveil the potential of identified novel hits as promising lead compounds for ROCK2 associated with cardiovascular diseases. These findings will further investigate via In-vitro and In-vivo studies to develop novel druglike molecules against ROCK2.

Identification of novel scaffolds targeting SIRT3 through molecular modeling techniques for the treatment of Hepatocellular carcinoma

Hepatocellular carcinoma is one of the top causes of cancer-related death globally. SIRT3 belongs to the Sirtuin family of proteins, a collection of NAD+-dependent enzymes that play a role in controlling several cellular functions, including metabolism, aging, and stress response. SIRT3 expression has been discovered to be often downregulated in HCC tissues relative to normal liver tissues. Hence, SIRT3 may function as a tumor suppressor in HCC. In the present study, pharmacophore-based virtual screening of a small molecule database was performed initially, and then the screened hits were docked to the active site of SIRT3 to choose the best binding modes. One co-crystal ligand (PDB name: 1NQ) was utilized as a template to generate pharmacophore model query. A total of 0.2 million compounds from the VITAS-M Lab database were downloaded and prepared for virtual screening. Following database preparation, ligand-based virtual screening was performed using the pharmacophore query model generated in the previous phase. The compounds with the same pharmacophoric characteristics as the query at the same distance were screened. There were a total of 74 hits that matched the query model. These compounds were then docked to the SIRT3 using the standard precision protocol of the glide tool. To select hits with high binding affinities, a threshold of −8 kcal/mol was used. Based on the glide gscore, two hits were chosen. These two hits were selected to investigate the stability of the protein-ligand complex by molecular dynamics simulation. All of these findings indicate that the selected hit compounds C1 and C2 can serve as lead compounds in inhibiting the biological activity of SIRT3 requiring further detailed investigations. Communicated by Ramaswamy H. Sarma

Identification of lead compound screened from the natural products atlas to treat renal inflammasomes using molecular docking and dynamics simulation

One of the most prevalent ailments is kidney disease. Effective therapies for chronic renal disease are hard to come by. As a result, there is significant clinical and social interest to predict and develop novel compounds to treat renal disorders. So, specific natural products have been employed in this study because they have protective effects against kidney diseases. When taken orally, natural products can help protect against or lessen the severity of the kidney damage caused by high fructose intake, a high-fat diet, and both Type I and Type 2 diabetes. Reduced podocyte injury, a contributor to albuminuria in diabetic nephropathy, reduces renal endothelial barrier function disruption due to hyperglycemia, as well as urinary microalbumin excretion and glomerular hyperfiltration. Multiple natural products have been shown to protect the kidneys from nephrotoxic chemicals such as LPS, gentamycin, alcohol, nicotine, lead, and cadmium, all of which can persuade acute kidney injury (AKI) or chronic kidney disease (CKD). Natural compounds inhibit regulatory enzymes for controlling inflammation-related diseases. For this, use computational methods such as drug design to identify novel flavonoid compounds against kidney diseases. Drug design via computational methods gaining admiration as a swift and effective technique to identify lead compounds in a shorter time at a low cost. In this in-silico study, we screened The Natural Product Atlas based on a structure-based pharmacophore query. Top hits were analyzed for ADMET analysis followed by molecular docking and docking validation. Finally, the lead compound was simulated for a period of 200 ns and trajectories were studied for stability. We found that NPA024823 showed promising binding and stability with the AIM2. This research work aims to predict novel anti-inflammatory compounds against kidney diseases to inhibit kidney inflammasome by targeting the AIM2 protein. So, in initial preclinical research, there will be lower failure rates that demonstrate safety profiles against predicted compounds. Communicated by Ramaswamy H. Sarma

Innovation of Fe(III), Ni(II), and Pd(II) complexes derived from benzothiazole imidazolidin‐4‐ol ligand: Geometrical elucidation, theoretical calculation, and pharmaceutical studies

The synthesis of a simple, highly tunable, and effective BSI ligand, 2‐(benzothiazol‐2‐ylimino)‐2,3‐dihydro‐1H‐imidazol‐4‐ol, was presented. Three new coordinating substances of BSI ligand were synthesized. Various spectroscopic and analytical methods, including 1H NMR and 13C NMR, infrared (IR), ultraviolet–visible (UV‐vis), thermal conduction, and measures of magnetism, were used to clarify the structures of these compounds. A further examination of the compounds revealed an octahedral‐coordinating environment surrounding the Fe3+ ion, ([Fe(BSI)2(NO3)2](NO3·0.5H2O)) and Ni2+, ([Ni(BSI)2(NO3)2](H2O)2) cations and distorted square planner surrounding Pd2+, ([Pd(BSI)(COOCH3)2]H2O) cation. The cations under investigation were linked to the BSI ligand through the nitrogen of the thiazole ring and NH of the imidazole ring. The formed BSI complexes' thermal deterioration behavior was investigated. Calculated kinetic data for the examined complexes' various phases of deterioration supported their endothermic character. Using the Gaussian 09 software at the B3LYP/LANL2DZ level, the equilibrium geometry of the ligands and their coordination complex has been studied by calculations using density functional theory (DFT). The suggested structures by DFT calculation are in good agreement with experimental data. The antibacterial effectiveness of the examined molecules against different types of bacteria and fungus reveals that the BSIPd complex (MIC = 2.25–4.75 μg/mL) has the greatest activity and is most comparable to the standard. The newly synthesized compounds were also tested against several cell lines using the MTT assay. The results are given as an IC50 value, where the Pd(II) complex values show the potential anticancer properties of the compound. Moreover, the inspected complexes showed significant cell growth inhibition activity (IC50 = 6.79–9.05 μg/mL), even higher than the standard anticancer drugs; cisplatin (IC50 = 18 μg/mL) versus breast carcinoma cells. This intriguing finding was verified by Swiss‐ADME and pharmacophore query calculations. In accordance with the actual findings, the in silico results showed that the free ligand's low activity increased when it complexed with the inspected metal ions.

Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer.

The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib's downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of -41.48 and -29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of -37.92 and -38.5 kJ/mol against ERBB and -41.2 and -46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies.

Drug Repurposing of FDA Compounds against α-Glucosidase for the Treatment of Type 2 Diabetes: Insights from Molecular Docking and Molecular Dynamics Simulations.

Type 2 diabetes mellitus is a chronic health problem that can be controlled by slowing one's carbohydrate metabolism by inhibiting α-glucosidase, an enzyme responsible for carbohydrate degradation. Currently, drugs for type 2 diabetes have limitations in terms of safety, efficiency, and potency, while cases are rapidly increasing. For this reason, the study planned and moved towards drug repurposing by utilizing food and drug administration (FDA)-approved drugs against α-glucosidase, and investigated the molecular mechanisms. The target protein was refined and optimized by introducing missing residues, and minimized to remove clashes to find the potential inhibitor against α-glucosidase. The most active compounds were selected after the docking study to generate a pharmacophore query for the virtual screening of FDA-approved drug molecules based on shape similarity. The analysis was performed using Autodock Vina (ADV)-based on binding affinities (-8.8 kcal/mol and -8.6 kcal/mol) and root-mean-square-deviation (RMSD) values (0.4 Å and 0.6 Å). Two of the most potent lead compounds were selected for a molecular dynamics (MD) simulation to determine the stability and specific interactions between receptor and ligand. The docking score, RMSD values, pharmacophore studies, and MD simulations revealed that two compounds, namely Trabectedin (ZINC000150338708) and Demeclocycline (ZINC000100036924), are potential inhibitors for α-glucosidase compared to standard inhibitors. These predictions showed that the FDA-approved molecules Trabectedin and Demeclocycline are potential suitable candidates for repurposing against type 2 diabetes. The in vitro studies showed that trabectedin was significantly effective with an IC50 of 1.263 ± 0.7 μM. Further investigation in the laboratory is needed to justify the safety of the drug to be used in vivo.

Computational study of nitro-benzylidene phenazine as dengue virus-2 NS2B-NS3 protease inhibitor.

According to the World Health Organisation (WHO), as of week 23 of 2022, there were more than 1,311 cases of dengue in Malaysia, with 13 deaths reported. Furthermore, there was an increase of 65.7% during the same period in 2021. Despite the increase in cumulative dengue incidence, there is no effective antiviral drug available for dengue treatment. This work aimed to evaluate several nitro-benzylidene phenazine compounds, especially those that contain 4-hydroxy-3,5-bis((2-(4-nitrophenyl)hydrazinylidene)-methyl)benzoate through pharmacophore queries selection method as potential dengue virus 2 (DENV2) NS2B-NS3 protease inhibitors. Herein, molecular docking was employed to correlate the energies of selected hits' free binding and their binding affinities. Pan assay interference compounds (PAINS) filter was also adopted to identify and assess the drug-likeness, toxicity, mutagenicity potentials, and pharmacokinetic profiles to select hit compounds that can be considered as lead DENV2 NS2B-NS3 protease inhibitors. Molecular dynamics assessment of two nitro-benzylidene phenazine derivatives bearing dinitro and hydroxy groups at the benzylidene ring showed their stability at the main binding pocket of DENV2 protease, where their MM-PBSA binding energies were between -22.53 and -17.01kcal/mol. This work reports those two nitro-benzylidene phenazine derivatives as hits with 52-55% efficiency as antiviral candidates. Therefore, further optimisation is required to minimise the lead compounds' toxicity and mutagenicity.

AI-based prediction of new binding site and virtual screening for the discovery of novel P2X3 receptor antagonists

Artificial intelligence (AI) has been recognized as a powerful technique that can accelerate drug discovery during the hit compound identification step. However, most simple deep learning models have been used for naive pre-filtering as the prediction result cannot be interpreted. Recently, our group developed a new deep learning model (Highlight on Target Sequence; HoTS) that can predict binding regions in a target protein sequence based on patterns learned from interactions between a target protein sequence and a ligand. In this study, we searched for new binding regions of the P2X3 receptor (P2X3R) using HoTS, and suggested a novel putative binding site of P2X3R by a cavity search on the predicted binding regions. The novel putative binding site was employed to generate pharmacophore features, and combinations of pharmacophore features were validated as queries. Two separate virtual screenings using the optimized pharmacophore query Q12 with docking-based scoring and HoTS-based prediction of ligand interactions enabled the initial selection of the compound library for in vitro screening. The screening of each set of 500 compounds from the two approaches (HoTS interaction prediction and Pharmacophore-LibDock cascade) resulted in the identification of 10 (HoTS-1 – 10) and 6 compounds (PD-1 – 6) with low micromolar IC50 values. Remarkably, the hit rate was 10-fold higher than that from the previous random screening of 8364 compound library, and the chemical structures of all identified hit compounds were distinct from those of known P2X3R antagonists, indicating that novel chemical entities could be developed for P2X3R antagonists by targeting the binding site. Overall, this study suggests the discovery of a novel putative binding site for P2X3R using the AI deep learning protocol along with in silico MD simulation and experimental screening of targeted library compounds to successfully identify 16 unique and novel hit compounds. These results may accelerate the discovery of novel chemical-class drugs for P2X3R antagonists.

Tailoring of some novel bis-hydrazone metal chelates, spectral based characterization and DFT calculations for pharmaceutical applications and in-silico treatments for verification

A series of new bis-hydrazone complexes was obtained from ((N'E,N'''E)-2,2′-(1,3-phenylenebis (oxy))bis(N'-(4,5-di-tert-butyl-2-hydroxybenzylidene)acetohydrazide)) ligand (BS) with Co2+, Cu2+, Ni2+ and Zn2+ ions. The structural elucidation of such compounds was achieved using elementary examination, spectral and magnetic experiments. Detailed inspection of complexes suggested a six-coordinating environment around Co2+, Cu2+ and Zn2+ cations and square planar around Ni2+ cation. The investigated cations were coordinated with the ligand via carbonyl oxygen of ketone group, nitrogen and other deprotonated oxygen atom. The thermal degradation behavior of the prepared bis-hydrazone complexes was studied. The kinetic data for the degradation stages of investigated complexes, were calculated and confirmed endothermic nonspontaneous degradation nature. The computational study was executed by an advanced software as Materials Studio package that elucidating the mode of bonding within the investigated metal chelates. The antimicrobial efficiency of the investigated molecules against several bacteria and fungi strains suggests that, the SBCu complex has the highest activity which closes to the reference. Furthermore, MTT assay was used to screen the newly synthesized compounds against a variety of cell lines. The results are expressed by IC50 value, in which the 48 µg/ml value of Cu(II) complex indicating its success as a potential anticancer agent. This interesting result was strengthen via computations by Swiss-ADME and pharmacophore query. The in-silico results exhibited the low activity of the free ligand which improved after complexation with the Cu(II) ion, in agreement with the practical results.

Discovery of Small-Molecule VapC1 Nuclease Inhibitors by Virtual Screening and Scaffold Hopping from an Atomic Structure Revealing Protein-Protein Interactions with a Native VapB1 Inhibitor.

Nontypeable Haemophilus influenzae (NTHi) are clinically important Gram-negative bacteria that are responsible for various human mucosal diseases, including otitis media (OM). Recurrent OM caused by NTHi is common, and infections that recur less than 2 weeks following antimicrobial therapy are largely attributable to the recurrence of the same strain of bacteria. Toxin-antitoxin (TA) modules encoded by bacteria enable rapid responses to environmental stresses and are thought to facilitate growth arrest, persistence, and tolerance to antibiotics. The vapBC-1 locus of NTHi encodes a type II TA system, comprising the ribonuclease toxin VapC1 and its cognate antitoxin VapB1. The activity of VapC1 has been linked to the survival of NTHi during antibiotic treatment both in vivo and ex vivo. Therefore, inhibitors of VapC1 might serve as adjuvants to antibiotics, preventing NTHi from entering growth arrest and surviving; however, none have been reported to date. A truncated VapB1 peptide from a crystal structure of the VapBC-1 complex was used to generate pharmacophore queries to facilitate a scaffold hopping approach for the identification of small-molecule VapC1 inhibitors. The National Center for Advancing Translational Sciences small-molecule library was virtually screened using the shape-based method rapid overlay of chemical structures (ROCS), and the top-ranking hits were docked into the VapB1 binding pocket of VapC1. Two hundred virtual screening hits with the best docking scores were selected and tested in a biochemical VapC1 activity assay, which confirmed eight compounds as VapC1 inhibitors. An additional 60 compounds were selected with structural similarities to the confirmed VapC1 inhibitors, of which 20 inhibited VapC1 activity. Intracellular target engagement of five inhibitors was indicated by the destabilization of VapC1 within bacterial cells from a cellular thermal shift assay; however, no impact on bacterial growth was observed. Thus, this virtual screening and scaffold hopping approach enabled the discovery of VapC1 ribonuclease inhibitors that might serve as starting points for preclinical development.

Effect of oxy-vanadium (IV) and oxy-zirconium (IV) ions in O,N-bidentate arylhydrazone complexes on their catalytic and biological potentials that supported via computerized usages

BackgroundBased on the high coordination behavior of arylhydrazones, as pincer chelating agents, the purpose of this research is to study the synthesis, characterization and reactivity of two mononuclear oxy-vanadium (IV) and oxy- zirconium (IV) complexes (VO(ALz)2 and ZrO(ALz)2, respectively) of O,N-monobasic bidenate arylhydazone derivative (2-((2-(2,4-dinitrophenyl) hydrazineylidene)methyl)-4-nitrophenol, HALz). MethodsVarious spectroscopic methods were applied to characterize the chemical structures of the ligand and their O=M4+-complexes (NMR, UV-Vis., Mass and IR spectra). Their reactivity was estimated catalytically and biologically. The significant findingsHere, the function of the oxy-highly charged metal ion of (O=M4+: V4+ and Zr4+-ions) on reactivity of their arylhydrazone complexes was reported catalytically and biologically. The differentiation in the catalytic features of VO(ALz)2 and ZrO(ALz)2 depends on the type of O=M4+ ion, which examined in the aerobic oxidation of benzyl alcohol using tert-butyl hydroperoxide (tBuOOH) under solvent free atmosphere at 90 °C (the optimized conditions). VO(ALz)2 exhibited little more progressed catalytic potential (2 h with 89% yield of benzaldehyde) over that of ZrO(ALz)2 (6 h with 82% yield of benzaldehyde). The electron-oxygen gain/loss of O=M4+ ion in its complex catalyst displayed the major role for progressing of its catalytic potential. The catalytic oxidation of secondary alcohols to their corresponded ketones was performed with VO(ALz)2 and ZrO(ALz)2 catalysts. A mechanistic pathway was proposed depending on via DFT approach and on spectroscopic aspects.The biological action of HALz, VO(ALz)2 and ZrO(ALz)2 were studied within their binding action towards ctDNA (through UV–Visible spectroscopy and viscosity measuring) depending on the type of O=M4+ ion in their reagents. The interaction of HALz, VO(ALz)2 and ZrO(ALz)2 and was evaluated with the binding constant (2.85, 6.07 and 5.42 × 105 mol−1 dm3, respectively), which referred to their high reactivity towards ctDNA. In addition, the values of Gibbs’ free energy supported their ctNDA interaction (-31.11, -32.99 and -32.71 kJ mol−1, respectively). Both V4+ and Zr4+ ions in their complexes promoted their reactivity as antioxidant, antimicrobial and anticancer reagents more that their uncoordinated HALz ligand. The interaction with DNA-pockets was investigated through in-silico ways regarding pharmacophore query and MOE-docking module, to strengthen the biological screening. Considerably, the current MO-complexes with their effective antimicrobial, antioxidant, and cytotoxicity activity would be probably appraised for further medicinal and pharmaceutical applications.

Synthesis and elucidation of binuclear thiazole-based complexes from Co(II) and Cu(II) ions: Conductometry, cytotoxicity and computational implementations for various verifications

A new thiazole-based ligand was prepared and investigated then used to preparing its Co(II) and Cu(II) complexes. All available analytical (CHN analysis & TGA) and spectral (IR, UV–Vis, 1H NMR, Mass, SEM, XRD & EDX) techniques were applied to elucidate the chemical formulae of new compounds. The ligand behaved as a neutral tetradentate towards binuclear metal ions in the two complex via N-H, two C = N and C-S groups. A tetrahedral geometry was suggested for Co(II) complex according to 4A2(F)→4T1(F)(ʋ3) transition at 15,873 cm−1. While, a square-planer geometry was suggested for Cu(II) complex according to 2B1g →2B2g (ʋ1) and 2B1g → 2Eg transitions. The magnetic moment values of the two complexes were appeared lower than the normal values, due to binuclear presence minimized electron spinning. The mass spectra of the complexes recorded their molecular ion peaks that match to the molecular formula after expel of crystal water molecules. A conductometry study was executed for the complex formed from nano-sized CuCl2 and the ligand in solution to extract the association and formation constants as well as the M : L molar ratio. The stereo structures of the ligand and its binuclear complexes were optimized by DFT method under valence double-zeta basis set. The distribution of N(1)-N(10), C(11)-S(12) and C(15)-N(13) groups is suitable for their coordination with the two metal ions without bond strain. The in vitro assay was performed for the new compounds against HePG2, PC3 and MCF-7 cancer cell lines. The two complexes exhibited high toxicity against breast cancer cells. This result was confirmed interestingly via in silico ways as pharmacophore query and MOE-docking. The interaction parameters and docking patterns reflect the superiority of Co(II) and Cu(II) complexes in controlling breast cancer cell which agree with that obtained in vitro.

Synthesis and characterization for new Mn(II) complexes; conductometry, DFT, antioxidant activity via enhancing superoxide dismutase enzymes that confirmed by in-silico and in-vitro ways

1- Synthesis and characterization for new simple Mn(II) complexes to be used for biological target 2- Conductometric titrations were carried out to estimate essential data for complex in solution 3- DFT study was conducted to optimize the structures and extract structural activity relationships 4- The catalytic behavior of Mn(II) complexes to enhance antioxidant function of superoxide dismutase (SOD) Two novel Mn(II) complexes were prepared from new simple ligands. The two complexes were isolated in the form of 1:1 molar ratio via coordination mode of neutral bidentate. This formula was suggested based on CHN, mass spectra and EDX analysis. HL 1 ligand coordinated by C=O and C=N groups, while H 2 L 2 ligand coordinated by C=O 13 and C-S groups. The tetrahedral geometry was the structural form suggested for the two Mn(II) complexes according to electronic transitions assign for 6 A 1 g→ 4 Eg(4D) and 6 A 1 g→ 4 T 1 g(4P). Conductometric titrations were carried out to estimate essential constants for the complex in solution sate. Using density-functional theory (DFT) via Gaussian 09 program, we optimized the structural forms of the ligands and their complexes. Valence double-zeta polarized basis set (6-31G*) and efficient core potential basis set (SDD) level were the two sets adjusted for optimizing the ligands and their Mn(II) complexes, respectively. The calculated parameters as well as the electrostatic potential maps (MEP) support the mode of bonding inside the complexes which agreed with the practical data. Also, functional activity relationships were obtained after calculating important physical parameters which suggest the superiority of two Mn(II) complexes in catalytic behavior with superoxide dismutase (SOD) enzyme. Interestingly, the antioxidant activity of the complexes was examined computationally (in-silico) and practically (in-vitro), to evaluate mimic MnSOD enzyme feature. Pharmacophore query was done according to ligand-based, to get a brief view about the ability of complexes to enhance SOD-enzyme function. The two complexes could being able to resident slightly the active core in 3cei and 2pgc proteins, which leads to improve antioxidant function of SOD-enzyme, to be mimic MnSOD-enzyme. This suggestion was further supported by MOE-docking approach which offered all interaction details. Moreover, in-vitro assay results exhibited antioxidant feature of the two complexes which reach up to 87% and surely considered promising. Finally, from in-silico and in-vitro assessments, we could introduce such two Mn(II) complexes as a mimic MnSOD enzyme in its antioxidant function.

The Psychonauts' Benzodiazepines; Quantitative Structure-Activity Relationship (QSAR) Analysis and Docking Prediction of Their Biological Activity.

Designer benzodiazepines (DBZDs) represent a serious health concern and are increasingly reported in polydrug consumption-related fatalities. When new DBZDs are identified, very limited information is available on their pharmacodynamics. Here, computational models (i.e., quantitative structure-activity relationship/QSAR and Molecular Docking) were used to analyse DBZDs identified online by an automated web crawler (NPSfinder®) and to predict their possible activity/affinity on the gamma-aminobutyric acid A receptors (GABA-ARs). The computational software MOE was used to calculate 2D QSAR models, perform docking studies on crystallised GABA-A receptors (6HUO, 6HUP) and generate pharmacophore queries from the docking conformational results. 101 DBZDs were identified online by NPSfinder®. The validated QSAR model predicted high biological activity values for 41% of these DBDZs. These predictions were supported by the docking studies (good binding affinity) and the pharmacophore modelling confirmed the importance of the presence and location of hydrophobic and polar functions identified by QSAR. This study confirms once again the importance of web-based analysis in the assessment of drug scenarios (DBZDs), and how computational models could be used to acquire fast and reliable information on biological activity for index novel DBZDs, as preliminary data for further investigations.

Molecular insight into isoform specific inhibition of PI3K-\u03b1 and PKC-\u03b7 with dietary agents through an ensemble pharmacophore and docking studies

Dietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, β-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from − 11.5 to − 8.5 kcal mol−1. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents.

Elucidation for coordination features of hydrazide ligand under influence of variable anions in bivalent transition metal salts; green synthesis, biological activity confirmed by in-silico approaches

Synthesis of new N′- cyclohexylidene-3‑hydroxy-2-naphthohydrazide (H2L) complexes was carried out by ball milling technique in the lack of solvent (green approach) and then characterized by analytical and spectroscopic techniques. The metal salts used for preparations, were varied in their conjugated anions (Cl−, SO4−2 & OAc−) to investigate the changes in properties of obtained complexes, by changing anions, even with the same ligand. The ligand was coordinated mainly as monobasic with the metal acetate salts, while a neutral with metal chloride or sulfate salts. Such coordination modes were appeared through bidentate or tridentate towards central metals within different molar ratios (1: 1 or 1:2, M:L). Conductometric study was performed for Co(II) complex to estimate the complex stoichiometry and either formation or association constants, in solution state. DMOL3 program was used via DFT/B3LYP method to optimize the studied compounds and to obtain essential quantum parameters. Consequently, we confirmed the coordination of O(11), O(13) and N(16) atoms according to their features appeared in molecular modeling study. In-silico assessment was performed to examine the interaction features of new compounds with pathogenic-DNA, before in-vitro screening. Such assessment was carried out firstly by pharmacophore query within MolPort drug-library to discover the analogues drugs in activity towards DNA proteins. MolPort-007–588–377 and MolPort -000–734–772 were the code numbers of two analogues drugs. Secondly MOE-docking process was executed to explain all interaction features and rank the inhibition activity of complexes. Furthermore, antimicrobial, antioxidant and antitumor activity were investigated for all compounds and Ni(II)-Bis(HL) complex showed excellent antioxidant activity. Whereas, Co(II)-Bis(HL) complex showed excellent cytotoxicity towards liver cancer cells. Finally, the whole characteristics of complexes were changed by changing conjugated anions, even with the same ligand.

Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation

Middle east respiratory syndrome coronavirus (MERS-CoV) is a fatal pathogen that poses a serious health risk worldwide and especially in the middle east countries. Targeting the MERS-CoV 3-chymotrypsin-like cysteine protease (3CLpro) with small covalent inhibitors is a significant approach to inhibit replication of the virus. The present work includes generating a pharmacophore model based on the X-ray crystal structures of MERS-CoV 3CLpro in complex with two covalently bound inhibitors. In silico screening of covalent chemical database having 31,642 compounds led to the identification of 378 compounds that fulfils the pharmacophore queries. Lipinski rules of five were then applied to select only compounds with the best physiochemical properties for orally bioavailable drugs. 260 compounds were obtained and subjected to covalent docking-based virtual screening to determine their binding energy scores. The top three candidate compounds, which were shown to adapt similar binding modes as the reported covalent ligands were selected. The mechanism and stability of binding of these compounds were confirmed by 100 ns molecular dynamic simulation followed by MM/PBSA binding free energy calculation. The identified compounds can facilitate the rational design of novel covalent inhibitors of MERS-CoV 3CLpro enzyme as anti-MERS CoV drugs.

Development of structure-based pharmacophore to target the β-catenin-TCF protein–protein interaction

β-catenin concentration is methodically controlled by the Wnt signaling pathway, wherein mutations of this pathway can cause aberrant activation leading to an influx of β-catenin, which is implicated in many cancers, specifically colon cancer. Targeting the β-catenin-TCF interface has become a popular strategy because of its role in the Wnt signaling transduction pathway, but efforts to push a small-molecule inhibitor to clinical success have been futile. In our current study, we attempted to identify druggable “hot spots” at the β-catenin-TCF interface by exploring plausible binding modes of a number of reported and chemically distinct inhibitors and defined their structure-based pharmacophore. Validation of our 4-feature pharmacophore hypothesis was carried out using another series of structure-related inhibitors with reported experimental data. Our hypothesis identified 73% of true actives with high enrichment of the most potent molecules in the test dataset. We speculate that our structure-based pharmacophore query may act as an in silico tool to rapidly screen small-molecule libraries for potentially new scaffolds to disrupt the β-catenin-TCF protein–protein interaction. In addition, our pharmacophore successfully identified actives from a set of structurally similar inhibitors and, ultimately, may be applied as an adjunct tool in the hit-to-lead optimization process.

Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach.

The ongoing pandemic caused by the novel coronavirus has been the greatest global health crisis since the Spanish flu pandemic of 1918. Thus far, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 1 million deaths, and there is no cure or vaccine to date. The recently solved crystal structure of the SARS-CoV-2 main protease has been a major focus for drug-discovery efforts. Here, we present a fragment-guided approach using ZINCPharmer, where 17 active fragments known to bind to the catalytic centre of the SARS-CoV-2 main protease (SARS-CoV-2 Mpro) were used as pharmacophore queries to search the ZINC databases of natural compounds and natural derivatives. This search yielded 134 hits that were then subjected to multiple rounds of in silico analyses, including blind and focused docking against the 3D structure of the main protease. We scrutinised the poses, scores, and protein–ligand interactions of 15 hits and selected 7. The scaffolds of the seven hits were structurally distinct from known inhibitor scaffolds, thus indicating scaffold novelty. Our work presents several novel scaffolds as potential candidates for experimental validation against SARS-CoV-2 Mpro.