Exploration of In-silico screening of therapeutic agents against SARS-CoV-2.

In the present investigation, molecular docking studies have been performed using AutoDock Vina to investigate the role of ligand-binding affinity at the hydrophobic pocket of COVID-19. The knowledge of the binding of protein receptors with ligand molecules is essential in drug discovery processes. Hydroxamic acids with reported biological activity, have been investigated for docking to an important target, SARS-CoV-2, in order to predict their therapeutic efficacy. The spike protein of the coronavirus is responsible for the attachment to host cells and a positive-sense single-strand RNA, (+)ssRNA, is a genetic material that can be translated into protein in the host cell. We modeled the structure of SARS-CoV-2 with the ligands, hydroxamic acids. They show binding capability with both, Spike protein and (+)ssRNA. The twain exhibit negative binding energies which signify that reactions are spontaneous, strong, and fast. The present research proposed hydroxamic acids as molecules which can be used for the development of anti-virals therapeutics against SARS-CoV-2.

In vitro investigation of biophysical interactions between Ag(I) complexes of bis(methyl)(thia/selena)salen and ct-DNA via multi-spectroscopic, physicochemical and molecular docking methods along with cytotoxicity study.

Four silver(I) (Ag(I)) complexes: 1.PF6 , 2.PF6 , 1.ClO4 and 2.ClO4 of bis(methyl)thia salen (1) and bis (methyl)selena salen (2) with two different counter anions (PF6 - and ClO4 - ) have been investigated for DNA binding properties. In vitro interactional association between the Ag(I) complexes and ct-DNA has been examined by performing spectroscopic titrations on absorption spectrophotometer and fluorescence spectrophotometer. A competitive binding study has also been done using a fluorescence spectrophotometer with ethidium bromide as a classical intercalator. The spectroscopic methods revealed a major groove. Viscometry and agarose gel electrophoresis experiments have also been performed as physicochemical methods to confirm the binding of complex molecules with DNA. Molecular docking analysis has been executed to obtain the theoretical insight into the mode of binding. The docking study demonstrated the major groove binding of all four complexes to the DNA with electrostatic metal-phosphate interactions (between the metal and the backbone of DNA) and hydrophobic interactions. Cytotoxicity of the complexes has been studied on the Human Fibroblast foreskin (HFF) cell line. The cytotoxicity results showed positive gesture for moving ahead to the next level of screening; the values were above 10 µM which are appreciated for the normal cell lines.

Explication of bovine serum albumin binding with naphthyl hydroxamic acids using a multispectroscopic and molecular docking approach along with its antioxidant activity.

In the present investigation, the protein-binding properties of naphthyl-based hydroxamic acids (HAs), N-1-naphthyllaurohydroxamic acid (1) and N-1-naphthyl-p-methylbenzohydroxamic acid (2) were studied using bovine serum albumin (BSA) and UV-visible spectroscopy, fluorescence spectroscopy, diffuse reflectance spectroscopy-Fourier transform infrared (DRS-FTIR), circular dichroism (CD), and cyclic voltammetry along with computational approaches, i.e. molecular docking. Alteration in the antioxidant activities of compound 1 and compound 2 during interaction with BSA was also studied. From the fluorescence studies, thermodynamic parameters such as Gibb's free energy (ΔG), entropy change (ΔS) and enthalpy change (ΔH) were calculated at five different temperatures (viz., 298, 303, 308, 313 or 318 K) for the HAs-BSA interaction. The results suggested that the binding process was enthalpy driven with dominating hydrogen bonds and van der Waals' interactions for both compounds. Warfarin (WF) and ibuprofen (IB) were used for competitive site-specific marker binding interaction and revealed that compound 1 and compound 2 were located in subdomain IIA (Sudlow's site I) on the BSA molecule. Conclusions based on above-applied techniques signify that various non-covalent forces were involved during the HAs-BSA interaction. Therefore the resulted HAs-BSA interaction manifested its effect in transportation, distribution and metabolism for the drug in the blood circulation system, therefore establishing HAs as a drug-like molecule.

DNA Folding Transition in Presence of Naphthylhydroxamic Acids as Revealed by Fluorescence Microscopic Single Molecule Observation Method.

Fluorescence microscopy is a field of growing applications in various fields as it can be used to study immunofluorescence,fluorescent proteins techniques, live-cell imaging and many more. The present investigation is based on this single molecule observation technique to observe the effect of N-arylhydroxamic acids on λ plasmid DNA and linear Bacteriophage T7 DNA. The compounds under present investigation include N-1-naphthyl-o-methylbenzohydroxamic acid,N-1-naphthyl-p-methylbenzohydroxamic acid, N-1-naphthyl ethoxy benzo hydroxamic acid, N-1-naphthylphenylacetohydroxamic acid and N-1-naphthyl valero hydroxamic acid. The hydrodynamic radius, RH of λ DNA and long-axis length, l of T7 DNA were determined from the direct observation of Brownian motion of the DNA molecules in the absence and presence of hydroxamic acids. Folding transition was observed for λ DNA as well as T7 DNA in the presence of naphthyl hydroxamic acids. N-1-naphthylvalerohydroxamic acid was found to be most effective.

In-vitro and in-silico analysis and antitumor studies of novel Cu(II) and V(V) complexes of N-p-Tolylbenzohydroxamic acid.

Copper(L2Cu) and vanadium(L2VOCl) complexes of N-p-tolylbenzohydroxamic acid (LH) ligand have been investigated for DNA binding efficacy by multiple analytical, spectral, and computational techniques. The results revealed that complexes as groove binders as evidenced by UV absorption. Fluorescence studies including displacement assay using classical intercalator ethidium bromide as fluorescent probe also confirmed as groove binders. The viscometric analysis too supports the inferences as strong groove binders for both the complexes. Molecular docking too exposed DNA as a target to the complexes which precisely binds L2Cu, in the minor groove region while L2VOCl in major groove region. Molecular dynamic simulation performed on L2Cu complex revealing the interaction of complex with DNA within 20 ns time. The complex stacked into the nitrogen bases of oligonucleotides and the bonding features were intrinsically preserved for longer simulation times. In-vitro cytotoxicity study was undertaken employing MTT assay against the breast cancer cell line (MCF-7). Potential cytotoxic activities were observed for L2Cu and L2VOCl complexes with IC50 values of showing 71 % and 74 % of inhibition respectively.

Interaction of cobalt(II) and copper(II) hydroxamates with polyriboadenylic acid: An insight into RNA based drug designing.

The polyadenylic acid [poly(A)] tail of mRNA plays a noteworthy role in the initiation of the translation, maturation, and stability of mRNA. It also significantly contributes to the production of alternate proteins in eukaryotic cells. Hence, it has recently been recognized as a prospective drug target. Binding affinity of bis(N-p-tolylbenzohydroxamato)Cobalt(II), [N-p-TBHA-Co(II)] (1) and bis(N-p-naphthylbenzohydroxamato)Copper(II), [N-p-NBHA-Cu(II)] (2) complexes with poly(A) have been investigated by biophysical techniques namely, absorption spectroscopy, fluorescence spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, circular dichroism spectroscopy, viscometric measurements and through molecular docking studies. The intrinsic binding constants (Kb) of complexes were determined following the order of N-p-TBHA-Co(II)] > N-p-NBHA-Cu(II), along with hyperchromism and a bathochromic shift for both complexes. The fluorescence quenching method revealed an interaction between poly(A)-N-p-TBHA-Co(II)/poly(A)-N-p-NBHA-Cu(II). The mode of binding was also determined via the fluorescence ferrocyanide quenching method. The increase in the viscosity of poly(A) that occurred from increasing the concentration of the N-p-TBHA-Co(II)/N-p-NBHA-Cu(II) complex was scrutinized. The characteristics of the interaction site of poly(A) with N-p-TBHA-Co(II)/N-p-NBHA-Cu(II) were adenine and phosphate groups, as revealed by DRS-FTIR spectroscopy. Based on these observations, a partial intercalative mode of the binding of poly(A) has been proposed for both complexes. Circular dichroism confirmed the interaction of both the complexes with poly(A). The molecular docking results illustrated that complexes strongly interact with poly(A) via the relative binding energies of the docked structure as -259.39eV and -226.30eV for N-p-TBHA-Co(II) and N-p-NBHA-Cu(II) respectively. Moreover, the binding affinity of N-p-TBHA-Co(II) is higher in all aspects than N-p-NBHA-Cu(II) for poly(A).

Quantitative structure-activity relationship (QSAR) of N-arylsubstituted hydroxamic acids as inhibitors of human adenocarcinoma cells A431.

Hydroxamic acids the multifunctional molecules with general formula R'-C(=O)NROH have interesting medicinal and biological potentiality. The antiproliferative activity of 12 hydroxamic acids has been tested in vitro towards human adenocarcinoma cell line by MTT assay. The IC(50) values were found to be in the range from 12 to 152.8 microM. The most potent product identified is N-p-chlorophenyl-4-nitrobenzohydroxamic acid with IC(50) value 12 microM. The RP-HPLC experiment of these molecules was performed with 50:50(V)/(V) % methanol - water mixture as mobile phase. A QSAR is developed for the human adenocarcinoma cells inhibitory activity of a series of hydroxamic acids (n=1-12) that are structurally related to hydroxyurea. Multivariate analytical tool, projection to latent structures was used to develop a suitably predictive model for the purpose of optimizing and identifying members with more potent inhibitory activity. The cross- validated Q(2)cum values for two optimal PLS models of hydroxamic acids are above 0.690 (remarkably higher 0.500), indicating good predictive abilities for log1/IC(50) values of HAs. By partial least squares regression, two QSAR models revealed that, besides the essential pharmacophore - NOH.C=O, retention capacity factor, logk', polar surface area, PSA, Dipole moment, Dm, total no. of hydrogen bond donor and acceptor atoms, H, and chlorine atoms attached in upper or/and lower phenyl rings, I(Cl) , are important determinants for the inhibitory potency against A431 cells.

Synthesis, characterization and nucleic acid binding studies of mononuclear copper(II) complexes derived from azo containing O, O donor ligands.

Azo linked salicyldehyde and a new 2-hydroxy acetophenone based ligands (HL1 and HL2) with their copper(II) complexes [Cu(L1)2] (1) and [Cu(L2)2] (2) were synthesized and characterized by spectroscopic methods such as 1H, 13C NMR, UV-Vis spectroscopy and elemental analyses. Calculation based on Density Functional Theory (DFT), have been performed to obtain optimized structures. Binding studies of these copper (II) complexes with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) were analyzed by absorption spectra, emission spectra and Viscosity studies and Molecular Docking techniques. The absorption spectral study indicated that the copper(II) complexes of 1 and 2 had intrinsic binding constants with DNA or RNA in the range of 7.6 ± 0.2 × 103 M-1 or 6.5 ± 0.3 × 103M-1 and 5.7 ± 0.4 × 104 M-1 or 1.8 ± 0.5 × 103 M-1 respectively. The synthesized compounds and nucleic acids were simulated by molecular docking to explore more details mode of interaction of the complexes and their orientations in the active site of the receptor.

Cu(I) complexes of bis(methyl)(thia/selena) salen ligands: Synthesis, characterization, redox behavior and DNA binding studies.

Mononuclear cuprous complexes 1 and 2, [{CH3E(o-C6H4)CH=NCH2}2Cu]ClO4; E=S/Se, have been synthesized by the reaction of bis(methyl)(thia/selena) salen ligands and [Cu(CH3CN)4]ClO4. Both the products were characterized by elemental analysis, ESI-MS, FT-IR, 1H/13C/77Se NMR, and cyclic voltammetry. The complexes possess tetrahedral geometry around metal center with the N2S2/N2Se2 coordination core. Cyclic voltammograms of complexes 1 and 2 displayed reversible anodic waves at E1/2=+0.08V and +0.10V, respectively, corresponding to the Cu(I)/Cu(II) redox couple. DNA binding studies of both the complexes were performed applying absorbance, fluorescence and molecular docking techniques. Competitive binding experiment of complexes with ct-DNA against ethidium bromide is performed to predict the mode of binding. The results indicate the groove binding mode of complexes 1 and 2 to DNA. The binding constants revealed the strong binding affinity of complexes towards ct-DNA.

RNA-Binding Efficacy of N-Phenylbenzohydroxamic Acid: An Invitro and Insilico Approach.

RNA has attracted recent attention for its key role in gene expression and hence targeting by small molecules for therapeutic intervention. This study is aimed to elucidate the specificity of RNA binding affinity of parent compound of N-arylhydroxamic acids series, N-phenylbenzohydroxamic acid trivially named as PBHA,C6H5NOH.C6H5CË­O. The binding behavior was examined by various biophysical methods such as absorption, fluorescence, and viscosity measurements. Molecular docking was also done. The value of affinity constant and overall binding constant was calculated 5.79±0.03×10(4) M(-1) and K'=1.09±0.03×10(5) M(-1), respectively. The Stern-Volmer constant Ksv obtained was 2.28±0.04×10(4) M(-1). The compound (PBHA) shows a concentration-based enhancement of fluorescence intensity with increasing RNA concentration. Fluorescence quenching of PBHA-RNA complex in presence of K4 [Fe(CN)6] was also observed. Viscometric studies complimented the UV results where a continuous increase in relative viscosity of the RNA solution was observed with added optimal PBHA concentration. All the experimental evidences indicate that PBHA can strongly bind to RNA through an intercalative mode.

Hydroxamic acids: proton donor and acceptor strength for use in drug design.

Hydroxamic acids, the naturally occurring and synthetic products, generally have low toxicities and are of interest for many therapeutic applications. The present investigation describes the measurement of hydrogen bond donor (HBD) strength of ten hydroxamic acids by measuring their log P(O/W) values. Hydroxamic acid functional group contains two oxygen and one nitrogen atom as the acceptor sites. Thus, HBA strength of these reagents is also computed. A knowledge of these parameters is valuable in the field of toxicology, pharmacology and environmental sciences.

Evaluation of lipophilicity of N-arylhydroxamic acids by reversed phase-high performance liquid chromatographic method and self-organizing molecular field analysis.

The RP-HPLC experiment of 19 N-arylsubstituted hydroxamic acids was carried out using a C18 (Hypersil Gold) column as a stationary phase and methanol-water mixture as mobile phase. The retention parameter, log k(w), was obtained by linear extrapolation of the logk' retention to pure water as the mobile phase. Self-organizing molecular field analysis (SOMFA), is used to generate three-dimensional quantitative structure-property relationship (3D-QSPR) models for log k(w) values of these set of molecules. The statistical results, cross-validation q(2) (0.859) and noncross-validation r(2) (0.878), show a satisfied predictive ability.

Molecular descriptors of N-arylhydroxamic acids: a tool in drug design.

The partition coefficient in the 1-octanol/water system, log P(O/W), is a measure of lipophilicity. It is used as a predictor of solute-membrane partitioning. The objective of this study was to measure the log P(O/W) of five hydroxamic acids. Other molecular descriptors of these solutes, namely molar volume, molar refraction, parachor, polarizability (pi*), hydrogen-bond donor acidity (epsilon alpha) and hydrogen-bond acceptor basicity (epsilon beta), have also been discussed. These properties represent the combined effects of a number of intermolecular forces between a solute and its environment.