Molecular modelling studies on adamantane-based Ebola virus GP-1 inhibitors using docking,pharmacophore and 3D-QSAR

The pathogenic Ebola virus (EBOV) causes a potential health risk and global spread. To date, few drugs are available for the treatment of Ebola virus disease (EVD) that allow researchers to use computational methods for designing potential drugs. The developed PHASE-based common six-point pharmacophore hypothesis (AADHPR_1) showed the necessity of two hydrogen bond acceptor features, one hydrogen bond donor feature, one hydrophobic group feature, one positively ionizable and one aromatic ring feature for further designing. We developed best 3D-QSAR models with high regression coefficients for the training (r²>0.82) and test (Q²>0.5) sets for both atoms-based and field-based 3D-QSAR models. The molecule 1A-4 (docking score = –4.711 kcal/mol) was obtained as best docked (SP mode) on Ebola virus envelope glycoprotein (PDB ID-3CSY) as compared with the standards oseltamivir (docking score = –4.39 kcal/mol) and zanamivir (docking score = –3.392 kcal/mol). The obtained ZINC hit ZINC58935541 showed a good docking score of –4.892 kcal/mol. The ZINC58935541 molecule also showed a strong binding affinity towards the receptor cavity of Ebola virus envelope glycoprotein when simulated for 1.2 ns. The good QikProp parameters reflect the fact that this molecule, upon optimization into a lead, might become a good candidate for the treatment of EVD.     

Design,DFT studies,antimicrobial and antioxidant potential of Binuclear N-heterocyclic Carbene (NHCs) complexes,Probing the aspect of DNA interaction through In-vitro and In-silico approach

N-heterocyclic carbene (NHC) adducts have shown remarkable biological potential for numerous medical applications. With an aim to improve biological potential of benzimidazolium salts, newer analogues of benzimidazole and their silver complexes were synthesized and characterized. Synthesized salts (L₁-L₂) and silver complexes (C₁-C₂) were confirmed through elemental analysis, UV–visible spectroscopy, FTIR, ¹H NMR & ¹³C NMR spectroscopy. The compounds C1 & C2 were found stable in solution form for studied time period when examined spectroscopically and showed optimum lipophilicity when measured for their partition coefficient through flask shake method. Synthesized compounds showed good antimicrobial potential against gram positive bacterial strain S. Aureus with IC₅₀ 2.02±0.12 and 2.11±0.13 µM respectively while 2.11±0.1 and 2.28±0.17 µM against gram negative bacterial strain E. Coli for C1 and C2 respectively. The interaction study of the related compounds with DNA was predicted by molecular docking study, which confirmed that the studied compound C1 (-8.04 kcal/mol) has a higher binding energy than compound C2 (-4.23 kcal/mol); Also, the compound C1 exhibits a better affinity against to DNA than Ethidium bromide (-7.68 kcal/mol) and cisplatin (-6.21 kcal/mol).The claim was practically assured through spectroscopic and viscometeric method which confirmed that compounds have good affinity for DNA with binding constant kb, 5.78×10⁴ M^-1 and 6.84×10⁴ M^-1 for C1 and C2 respectively.     

Synthesis and greener pastures biological study of bis-thiadiazoles as potential Covid-19 drug candidates

A novel series of bis- (Abdelhamid et al., 2017, Banerjee et al., 2018, Bharanidharan et al., 2022)thiadiazoles was synthesized from the reaction of precursor dimethyl 2,2′-(1,2-diphenylethane-1,2-diylidene)-bis(hydrazine-1-carbodithioate) and hydrazonyl chlorides in ethanol under ultrasonic irradiation. Spectral tools (IR. NMR, MS, elemental analyses, molecular dynamic simulation, DFT and LUMO and HOMO) were used to elucidate the structure of the isolated products. Molecular docking for the precursor, 3 and ligands 6a-i to two COVID-19 important proteins M^pro and RdRp was compared with two approved drugs, Remdesivir and Ivermectin. The binding affinity varied between the ligands and the drugs. The highest recorded binding affinity of 6c with M^pro was (?9.2 kcal/mol), followed by 6b and 6a, (?8.9 and ?8.5 kcal/mol), respectively. The lowest recorded binding affinity was (?7.0 kcal/mol) for 6 g. In comparison, the approved drugs showed binding affinity (?7.4 and ?7.7 kcal/mol), for Remdesivir and Ivermectin, respectively, which are within the range of the binding affinity of our ligands. The binding affinity of the approved drug Ivermectin against RdRp recoded the highest (?8.6 kcal/mol), followed by 6a, 6 h, and 6i are the same have (?8.2 kcal/mol). The lowest reading was found for compound 3 ligand (?6.3 kcal/mol). On the other side, the amino acids also differed between the compounds studied in this project for both the viral proteins. The ligand 6a forms three H-bonds with Thr 319(A), Sr 255(A) and Arg 457(A), whereas Ivermectin forms three H-bonds with His 41(A), Gly143(A) and Gln 18(A) for viral M^pro. The RdRp amino acids residues could be divided into four groups based on the amino acids that interact with hydrogen or hydrophobic interactions. The first group contained 6d, 6b, 6 g, and Remdesivir with 1–4 hydrogen bonds and hydrophobic interactions 1 to 10. Group 2 is 6a and 6f exhibited 1 and 3 hydrogen bonds and 15 and 14 hydrophobic interactions. Group 3 has 6e and Ivermectin shows 4 and 3 hydrogen bonds, respectively and 11 hydrophobic interactions for both compounds. The last group contains ligands 3, 6c, 6 h, and 6i gave 1–3 hydrogen bonds and 6c and 3 recorded the highest number of hydrophobic interactions, 14 for both 6c and 6 h. Pro Tox-II estimated compounds’ activities as Hepatoxic, Carcinogenic and Mutagenic, revealing that 6f-h were inactive in all five similar to that found with Remdesivir and Ivermectin. The drug-likeness prediction was carried out by studying physicochemical properties, lipophilicity, size, polarity, insolubility, unsaturation, and flexibility. Generally, some properties of the ligands were comparable to that of the standards used in this study, Remdesivir and Ivermectin.     

Evaluation of in vitro,in silico antidiabetic and antioxidant potential of bioactivity based isolated “Pakistanine” from Berberis baluchistanica

Bioassay based fractionation of methanolic extract of Berberis baluchistanica (Berberidaceae), used traditionally for internal injuries, led to the isolation of known compounds (1–4). The structure of these compounds was elucidated by different spectroscopic analysis and available literature data. Antidiabetic and antioxidant potentials of B. baluchistanica fractions and isolated compounds were evaluated using in vitro alpha- amylase and DPPH assays. The isolated compounds were identified as obamegine (1), pakistanine (2), 8-oxyberberine (3) and baluchistine (4). Obamegine was reported from many other species of this genus but it is first time isolated from B. baluchistanica in present study. Moreover, in vitro pakistanine (2) was found as bioactive lead molecule for hypoglycemic (IC₅₀:40.26 µg/ml) and antioxidant (IC₅₀:14.15 µg/ml) activities compared to acarbose (IC₅₀:33.68 µg/ml) and ascorbic acid (IC₅₀:0.41 µg/ml). To the best of our knowledge, no previous data were available for these biological activities. Additionally, in silico antidiabetic and antioxidant activity of pakistanine against two proteins, α-amylase (-9.7 kcal/mol) and tyrosinase (-8.7 kcal/mol) are reported here for the first time. The molecular docking binding interactions authenticate and support the above-mentioned activities and are helpful in predicting the mechanism of action of pakistanine (2).     

The structure of dihydropyrroloindoles: A quantum-chemical estimation of conjugation in cyclohexadiene systems

A non-empirical quantum chemical calculation of isomeric 3,6-divinyl-3,4,5,6-tetrahydropyrrolo[3,2-e] indole 1 and 1,5-divinyl-1,4,5,8-tetrahydro[3,2-f]indole 2 structures carried out by DFT (B3LYP) method with 6-311++G(d, p) and 6-311++G(3df, p) basis sets showed the energy preference of 2 over 1 (1.33 kcal/mol and 1.47 kcal/mol, respectively). The structure of the molecule of 2 is planar while the molecule of 1 is non-planar due to the presence of sp ³-hybridized carbon atoms.     

Hydroesterification of cyclohexene using the complex Pd(PPh3)2(TsO)2 as catalyst precursor: Effect of a hydrogen source (TsOH,H2O) on the TOF and a kinetic study (TsOH: p-toluenesulfonic acid)

The hydroesterification of cyclohexene is catalyzed by a preformed Pd(PPh₃)₂(TsO)₂ complex I in methanol as solvent. The effect of PPh₃, TsOH, and water on the TOF has been evaluated. The system I/PPh₃/TsOH=1/6/8, in the presence of 800 ppm of H₂O, at 373 K and under 2.0 MPa of CO leads to a TOF as high as 850 h⁻¹. The increase of TOF observed adding a hydride source such as TsOH and H₂O suggests that Pd-hydride species plays a key role in the first step of the catalytic cycle. The initial reaction rate increases linearly with the concentration of cyclohexene and of MeOH and passes through a maximum with increasing the pressure of CO. The rate equation r₀=k₁P_CO (1+k₂P_CO+k₃P_CO²)⁻¹ fits well the experimental data. The values of k₁, k₂, and k₃ have been evaluated at different temperatures. From the plot ln k versus 1/T, E₁=19.4 kcal/mol, E₂=20.6 kcal/mol and E₃=6.5 kcal/mol have been evaluated. On the basis of experimental evidences and of the kinetic study, a catalytic cycle mechanism has been proposed.     

Synthetic and structural studies of [6]-, [7]- and [10]metacyclophanes

A new preparative sequence from 2,3-polymethylene-2-cyclopentenone 5 to 2,6-polymethylenebromobenzenes 3 (n = 6, 7, 10) and 2,6-polymethylenephenyllithiums 6 has been found. The reaction of 6 with various electrophiles produces a number of new compounds to disclose the unique reactivity of the aryl C-Li moiety surrounded by the polymethylene chain. Photolysis of 3a and 3b provides transannular products 8, 10 and 11, all arising from the proximity between the aromatic bromine and the aliphatic hydrogen intraannularly opposed to be removed as HBr. Spectrometric study gives quantitative data of the dependence of the molecular geometry upon the chain length and the aromatic substituents. The energy barriers ΔG_c^≠ of the conformational flipping are 17·4 kcal/mol (T_c 76·5°) for [6]metacyclophane (7a), 11·5 kcal/mol (T_c ?28°) for [7]metacyclophane (7b), ·8 kcal/mol for [10]metacyclophane (7c). The lower-energy process of the aliphatic chain in [6]metacyclophane derivatives is the pseudorotation with substituent-dependent barrier ΔG_c^≠ 11·1 kcal/mol (T_c ?31·5°) for 7a, 12·4 kcal/mol (T_c ?4·5°) for 3a and 12·7 kcal/mol (T_c 1·0°) for 12a. The rather large rotational barrier is attributed to the compressed structure of each system. The benzene ring distortion of the cyclophanes is deduced from the bathochromic shift of the B-band and the diamagnetic shift of the benzene proton signals in the PMR.     

Conformational przferknce of the S→O bond. 1H and 13C NMR studies of the mono-S-oxides of 1,2-, 1,3- and 1,4-dithianes

The ¹H and ¹³C NMR behavior of the monosulfoxides of 1,2-, 1,3-and 1,4-dithianes (1–3) were studied in order to determine the conformational preference of the S→O bond in these heterocycles. From the results of variable temperature, double irradiation, solvent effects and shift reagent experiments, It is concluded that the axial conformers dominate the conformational equilibria of 1 and 3. On the other hand, 2-equatorial is more stable than 2-axial by 0.64 kcal/mol (ΔG°) at -80°, in CD₃OD. This value is essentially identical with the one determined in CHClF₂, and the lack of a solvent effect appears to indicate that dipole/dipole interactions do not control this equilibrium. AΔG_c³ = 11.0 kcal/mol was determined for the inversion process of 2. Complete ¹H and ¹³C NMR assignments for 1–3 are presented.     

A DFT study on geometric preference of non-bridging form to bridging form in molybdenum complexes with phosphenium ligand

Density functional theory (DFT) calculations were conducted to elucidate why complexes bearing both phosphenium and phosphite ligands in a cis position do not take an OR-bridging form and why complexes bearing both silylene and alkoxysilyl ligands in a cis position prefer an OR-bridging form. Energy profiles, geometries, and electronic structures along the transformation pathways from the non-bridging to the bridging forms were analyzed for four phosphenium phosphite complexes, cis-[Mo(CO)₄{P(NMeCH₂)₂}{P(NMeCH₂)₂(OMe)}]⁺ (1), CpMo(CO){P(NMeCH₂)₂}{P(NMeCH₂)₂(OMe)} (2), CpMo(CO){PMe₂}{PMe₂(OMe)} (3), cis-[Mo(CO)₄(PR₂){PR₂(OMe)}]⁺ (R = Me, Et, n-Pr) (4), and a silylene alkoxysilyl complex CpMo(CO)₂{(SiMe₂)₂(OMe)} (Si1). The DFT B3LYP/SBKJC(d) calculations for phosphenium phosphite complexes 1 and 2 revealed that there are two local minima (LM), both of which are non-bridging forms with similar energy levels, and one bridging form as a transition state (TS), which connects one non-bridging form and its mirror-image complex. These are consistent with the experimental results. In contrast, for silylene alkoxysilyl complex Si1, both bridging and non-bridging forms are LM. The former is more stable than the latter by 21.07 kcal/mol. The TS directly connects them in association with the rotation of the silyl ligand. The quite small activation energy less than 2 kcal/mol and the large energy difference between the two LM are consistent with the experimental results that only the bridging form has been reported to date. Phosphenium phosphite complexes 3 and 4 with alkyl substituents in place of amino substituents on the phosphenium P were also subjected to DFT calculations. The energy profile of 3 was found to be similar to those of 1 and 2. However, non-bridging and bridging forms were both LM for 4. The bridging form was estimated to be easily transformed to the non-bridging form, because the non-bridging form is more stable in energy and the activation energy from the bridging form is less than 1 kcal/mol for 4a. Charge accumulation in the bonding region, nuclear repulsion among the ligands, and the stability of E–O–E bond formation (E = P, Si) were considered to be decisive factors for the geometric feature.     

Computational Approaches for the Design of Novel Anticancer Compounds Based on Pyrazolo[3,4-d]pyrimidine Derivatives as TRAP1 Inhibitor

In the present in-silico study, various computational techniques were applied to determine potent compounds against TRAP1 kinase. The pharmacophore hypothesis DHHRR_1 consists of important features required for activity. The 3D QSAR study showed a statistically significant model with R² = 0.96 and Q² = 0.57. Leave one out (LOO) cross-validation (R² CV = 0.58) was used to validate the QSAR model. The molecular docking study showed maximum XP docking scores (−11.265, −10.532, −10.422, −10.827, −10.753 kcal/mol) for potent pyrazole analogs (42, 46, 49, 56, 43), respectively, with significant interactions with amino acid residues (ASP 594, CYS 532, PHE 583, SER 536) against TRAP1 kinase receptors (PDB ID: 5Y3N). Furthermore, the docking results were validated using the 100 ns MD simulations performed for the selected five docked complexes. The selected inhibitors showed relatively higher binding affinities than the TRAP1 inhibitor molecules present in the literature. The ZINC database was used for a virtual screening study that screened ZINC05297837, ZINC05434822, and ZINC72286418, which showed similar binding interactions to those shown by potent ligands. Absorption, distribution, metabolism, and excretion (ADME) analysis showed noticeable results. The results of the study may be helpful for the further development of potent TRAP1 inhibitors     

Design of a new axially chiral molecule by conformational fixation: 2,6-dithiaspiro[3.3]heptane 2,6-dioxide and its heavier analogues

We have designed a new axially chiral bis(sulfoxide) molecule with conformational rigidity: 2,6-dithiaspiro[3.3]heptane 2,6-dioxide 2a. This molecule has axial asymmetry due to two puckered thietane ring systems. The lone pairs on the sulfur show a strong s-character, which was expected to result in a high barrier to racemization, that is, inversion at the sulfur. We confirmed this prediction by calculations and experimentation. The lone pairs of the sulfur in 2a are sp^1.00 and the enthalpy of activation (ΔH³) for inversion is 47.5 kcal/mol (B3LYP/6-31G(d)). The ¹H NMR spectra of 2a showed two doublets and two doubled doublet peaks, which resulted from the rigidity of the four-membered ring frameworks without flipping. We separated the enantiomers of 2a by HPLC with a chiral stationary phase column to observe a set of complementary peaks. We also calculated the diselena- and ditellura congeners and confirmed that they also show axial chirality.     

Assessment of antimicrobial and enzymes inhibition effects of Allium kastambulense with in silico studies: Analysis of its phenolic compounds and flavonoid contents

Type 2 diabetes and obesity-related metabolic diseases have been treated with traditional medicinal plants for centuries. In this study, the effects of Allium kastambulense plant extracts on different enzyme activities were investigated, and the results were added as graphics and tables after calculating. This study aimed to identify and quantify the phenolic composition of Allium kastambulense Bosse and determine the anti-lipase, anti-urease, anti-melanogenesis, antidiabetic, anti-alzheimer, and antibacterial properties. IC₅₀ results for all enzymes were obtained between 0.55 and 138 µg/mL, and this plant inhibited HMG_CoA R and tyrosinase enzymes more with IC₅₀ values of 0.55 and 59.17 µg/mL, respectively. The interactions of active compounds showing activity against different enzymes were examined with molecular docking studies. The most active compound 3, (rosmarinic acid) has ?10.90 kcal/mol binding energy value against HMG_CoA R, and also the potential structure compound 2, (+catechin), which has activity against α-amylase, α-glycosidase, and lipase enzymes, was –8.30, ?8.40 and ?9.70 kcal/mol, respectively. Finally, antimicrobial effects, total phenolic, and flavonoid content, determined with its higher total phenolic (22.63 mg GAE/g extract) and flavonoid (6.41 mgQE/g extract) contents and main chemical compounds of this plant were gentisic acid, (+) catechin, and rosmarinic acid, respectively.     

Vinylidene carbonylation at a manganese-iron complex: A density functional study of mechanism

Treating the phenylvinyldene manganese complex Cp(CO)₂MnC¹C²HPh, 1, with [Fe(CO)₄] yields the binuclear μ-vinylidene complex Cp(CO)₂MnFe(μ-C¹C²HPh)(CO)₄, 2, that further isomerizes to the carbonylated product η⁴-[Cp(CO)₂MnC¹(CO)C²HPh]Fe(CO)₃, 3. In a computational study of the mechanism using a hybrid density functional method, we considered two stereoisomers for species 2 and 3 where the phenyl group at center C² is oriented in cis (E form) or trans (Z form) fashion to the Cp(CO)₂Mn unit. Isomers 2E and 2Z were calculated to be degenerate whereas the experimentally detected species 3E is 8 kcal/mol more stable than its isomer 3Z. The two-step pathway 1 → 2Z → 3E was calculated to be the lowest-energy route with the highest activation barrier at 12 kcal/mol. The activation energy of the alternative single-step pathway 1 → 3E is 19 kcal/mol. We rationalized the stabilization of the ground state of 3E and the transition states leading to or starting from isomer 2Z as conjugation effect between the Mn-CC metallaallene fragment and the co-planar phenyl ring.     

A study on interaction of Be, Mg and Ca with phenylalanine: Binding energies, metal ion affinities and IR signature of complex stability

The interaction between divalent metal cations and amino acids plays an important role in many biological processes. In present report, we have examined the effect of metal cations (Be⁺⁺, Mg⁺⁺ and Ca⁺⁺) interaction on structures, binding energies (BE), metal ion affinities (MIA) and infrared (IR) spectra of phenylalanine (Phe) molecule by density functional theory (DFT) calculations at B3LYP/6-311++G(d,p) level. Nine different ground state isomers of Phe molecule have been optimized at B3LYP/6-311++G (d,p) level of theory. The relative ground state energies of these nine isomers are lying between 0.0-1.9 kcal/mol with respect to the ground state energy of most stable Phe isomer. Seven most stable complexes of Phe molecule with Be⁺⁺, Mg⁺⁺ and Ca⁺⁺ [Phe+M]⁺⁺ (M = Be⁺⁺, Mg⁺⁺ and Ca⁺⁺) were studied. The calculated values of metal ion affinity (MIA), BE and the Gibbs free energies of each [Phe+M] ⁺⁺ complexes were found to be in the order of Be⁺⁺ > Mg⁺⁺ > Ca⁺⁺. Among the seven [Phe+M]⁺⁺ complexes, the most stable conformer has charge solvation structure where the metal cations coordinated through tridentate bonds with -N, -O atoms and benzene ring (N/O/Ring). The [Phe+Be]⁺⁺ complex has maximum MIA value, 353.3 kcal/mol than that of [Phe+Mg]⁺⁺ and [Phe + Ca]⁺⁺ complexes. Thus, the complex [Phe+Be]⁺⁺ is energetically more stable than that of [Phe+Mg]⁺⁺ and [Phe + Ca]⁺⁺. The IR spectra of each seven conformers of [Phe+M]⁺⁺ complexes have been also calculated. The wavnumber position of (-CO) stretching mode was used to determine the charge/salt bridge structures of the [Phe+M]⁺⁺ complex. The most stable [Phe+M]⁺⁺ complex has been also verified through the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) analysis.     

Ring contraction mechanisms in substituted cyclohexylium cations

The effect of an electron donating or withdrawing group on the ring contraction mechanism of a cyclohexylium (cyclohexane-derived) cation has been studied using density functional theory. The barrier to rearrangement of the parent cyclohexane cation (1) was previously calculated to be 7.7 kcal/mol using PBE/6-311++G(2d, 2p). We show in this work that addition of an electron withdrawing group (CF₃) lowers the average barrier to ring contraction, while an electron donating group (CH₃) increases the average barrier, relative to the parent, unsubstituted, cyclohexane cation. Calculated barrier heights for going from a 6-membered to 5-membered ring range from 4.3 to 23.3 kcal/mol for methyl-cyclohexylium (2), but only from 0.6 to 14.0 kcal/mol for trifluoromethyl-cyclohexylium (3). The lower barriers for 3 can be explained by (a) the starting structures involved, and (b) the use of dative bonding as a catalyst in stabilizing intermediates and transition states. For 1 and 3 the reaction involves starting from secondary cations and going downhill in energy through secondary intermediates to a tertiary product. However, 2 does not benefit from such favorable energetics since it more likely starts from a tertiary cation and has to first rearrange to secondary intermediates to derive the tertiary methyl-cyclopentane-type product.     

Substituted six-membered ring carbenes: the effects of amino and cyclopropyl groups through DFT calculations

DFT calculations are employed to compare and contrast six-membered ring carbenes including 1,3-dimethyltetrahydropyrimidin-2-ylidene (1a), 1-methyl-3-cyclopropyltetrahydropyridine-2-ylidene (2a), and 1,3-dicyclopropylcyclohexane-2-ylidene (3a) as well as their unsaturated analogues 1b, 2b, 3b, and 2c. The amino groups exert singlet-triplet energy separation (?E_s−t) of 60.9 kcal/mol to 1a while cyclopropyls induce a ?E_s−t of 14.8 kcal/mol to 3a. The simultaneous presence of amino and cyclopropyl in 2a leads to a ?E_s−t of 43.3 kcal/mol. Unsaturation slightly increases the ?E_s−t of 1a and 3a but not that of 2a. Our thermodynamic, kinetic, and reactivity results are compared with those of synthetic five-membered ring N-heterocyclic carbenes.     

The structure and racemization of 1,2-bis(pentaphenylphenyl)benzene

1,2-Bis(pentaphenylphenyl)benzene (2) was synthesized by the cycloaddition of 1,2-bis(phenylethynyl)benzene and tetracyclone. Its X-ray structure was determined, and the molecule adopts a C₂-symmetric conformation in the crystal. Monomethoxy and dimethoxy derivatives of compound 2 were also prepared, and dynamic NMR studies of these compounds yielded a free energy of activation for racemization (ΔG³_rac) of 20.3?kcal/mol at 423?K. The results are compared with estimates of ΔG³_rac for 2 by various DFT methods.