Impact of Olive Oil Constituents on C-reactive Protein: In silico Evidence.

Pain is a sensation a humans sense as a protective mechanism against physical injury. This sensation is closely related to inflammation. It ranges from mild to highly obnoxious. It is well-known that the levels of the inflammatory biomarker, C-reactive protein (CRP), increase manifold in acute inflammation and pain. Olive oil, known to have many phytochemicals, has been traditionally used to alleviate pain. Amongst major phenolic compounds in olive oil are oleuropein (OLE), hydroxytyrosol (HT), tyrosol, and oleocanthal. Whether the analgesic and anti-inflammatory properties in olive oil are due to any specific interections is not known. Therefore, this study aimed to elucidate the possible anti-inflammatory and anti-nociceptive properties in those major phenolic compounds by using molecular docking software MOE 2015, comparing the energy value and binding site of phenolic compounds to that of well-known synthetic non-steroidal anti-inflammatory drugs (NSAIDs) and phosphocholine. The docking experiment showed that all compounds could directly interact with CRP. Oleuropein had the most potent interaction with CRP (-7.7580), followed by indomethacin (-6.0775), oleocanthal (-5.5734), ibuprofen (-5.3857), phosphocholine (-4.3876), HT (-4.2782), and tyrosol (-4.2329). Interestingly, the present study found other phytochemicals in olive oil that can be exploited as potential, safe, and cost-effective lead compound(s) for analgesic and anti-inflammatory activity, as supported by its molecular docking data.

Pharmacophore study, molecular docking and molecular dynamic simulation of virgin coconut oil derivatives as anti-inflammatory agent against COX-2.

Background: Virgin coconut oil is mostly made up of saturated fatty acids in which approximately 72% are medium chain triglycerides. Medium chain triglycerides can be digested into medium chain fatty acids and medium chain monoglycerides which are bioactive components. Therefore, it is very important to study the in-silico ability of some Virgin coconut oil derivatives, namely, medium chain fatty acids and medium chain monoglycerides to inhibit Cyclooxygenase 2 (COX-2) protein for prevention of excessive inflammatory response. Results: Pharmacophore study displayed monolaurin with two hydrogen bond donor, three hydrogen bond acceptor and five hydrophobic interactions, while lauric acid presented two hydrogen bond acceptor, five hydrophobic interactions and a negative ion interaction. Molecular docking underlined the ability of monolaurin in the inhibition of COX-2 protein which causes inflammatory action with a decent result of energy binding affinity of - 7.58 kcal/mol and 15 interactions out of which 3 are strong hydrogen bond with TYR385 (3.00 Å), PHE529 (2.77 Å), and GLY533 (3.10 Å) residues of the protein. Monolaurin was employed as hydrogen bond acceptor to the side of residue TYR385 of COX-2 protein with an occupancy of 67.03% and was observed to be long-living during the entire 1000 frames of the molecular dynamic simulation. The analysis of RMSD score of the Monolaurin-COX-2 complex backbone was calculated to be low (1.137 ± 0.153 Å) and was in a stable range of 0.480 to 1.520 Å. Redocking of this complex still maintained a strong hydrogen bond (2.87 Å) with the main residue TYR385. AMDET results where promising for medium chain fatty acids and medium chain monoglycerides with good physicochemical drug scores. Conclusions: This can be concluded from the results obtained that the monolaurin has strong interactions with COX-2 protein to disrupt its function due to significant hydrogen bonds and hydrophobic interactions with amino acid residues present in the target protein's active site. These results displayed a very significant anti-inflammatory potential of monolaurin and a new promising drug candidates as anti-inflammatory agent.

Pharmacophore modelling of vanillin derivatives, favipiravir, chloroquine, hydroxychloroquine, monolaurin and tetrodotoxin as MPro inhibitors of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

OBJECTIVES: The aim of this study was to use Ligand-based pharmacophore modelling approach for four established antiviral drugs, namely remdesivir, lopinavir, ritonavir and hydroxychloroquine for COVID-19 inhibitors as training sets. In this study Twenty vanillin derivatives together with monolaurin and tetrodotoxin were used as test sets to evaluate as potential SARS-CoV-2 inhibitors. The Structure-based pharmacophore modelling approach was also performed using 5RE6, 5REX and 5RFZ in order to analyse the binding site and ligand-protein complex interactions. RESULTS: The pharmacophore modelling mode of 5RE6 displayed two Hydrogen Bond Acceptors (HBA) and one Hydrophobic (HY) interaction. Besides, the pharmacophore model of 5REX showed two HBA and two HY interactions. Finally, the pharmacophore model of 5RFZ showed three HBA and one HY interaction. Based on ligand-based approach, 20 Schiff-based vanillin derivatives, showed strong MPro inhibition activity. This was due to their good alignment and common features to PDB-5RE6. Similarly, monolaurin and tetrodotoxin displayed some significant activity against SARS-CoV-2. From structure-based approach, vanillin derivatives (1) to (12) displayed some potent MPro inhibition against SARS-CoV-2. Favipiravir, chloroquine and hydroxychloroquine also showed some significant MPro inhibition.

Polymer Based Protein Therapeutics.

Proteins have played a very important role in the drug industry for developing treatments of various diseases such as auto-immune diseases, cancer, diabetes, mental disorder, metabolic disease, and others. Therapeutic proteins have high activity and specificity but they have some limitations such as short half-life, poor stability, low solubility and immunogenicity, so they cannot prolong their therapeutic activity. These shortcomings have been rectified by using polymers for the conjugation with proteins. The conjugates of protein-polymer improves the half-lives, stability and makes them non-immunogenic. Poly(ethylene glycol) (PEG), is widely used in the delivery of proteins because it is the current gold standard for stealth polymers in the emerging field of polymer-based delivery as compared to various biodegradable polymers. PEGylation enhances the retention of therapeutic proteins, effectively alters the pharmacokinetics and enhances the pharmaceutical value. Smart polymer have been used to cope with the pathophysiological environment of target site and have imposed less toxic effects.The contents of this article are challenges in formulation of therapeutic proteins, synthetic routes of conjugates, smart polymer-protein conjugates and also some advantages/disadvantages of polymers as a carrier system of proteins.

n-Butyldichlorido{4-cyclo-hexyl-1-[1-(pyridin-2-yl-κN)ethyl-idene]thio-semi-carb-azi-dato-κ²N¹,S}tin(IV).

Two independent mol-ecules comprise the asymmetric unit in the title compound, [Sn(C4H9)(C14H19N4S)Cl2]. In each mol-ecule, the Sn(IV) atom exists within a distorted octa-hedral geometry defined by the N,N',S-tridentate mono-deprotonated Schiff base ligand, two mutually trans Cl atoms, and the α-C atom of the n-butyl group; the latter is trans to the azo-N atom. The greatest distortion from the ideal geometry is found in the nominally trans angle formed by the S and pyridyl-N atoms at Sn [151.72 (7) and 152.04 (7)°, respectively]. In the crystal, mol-ecules are consolidated into a three-dimensional architecture by a combination of N-H⋯Cl, C-H⋯π and π-π inter-actions [inter-centroid distances = 3.6718 (19) and 3.675 (2) Å].

3-{(E)-[1-(2-Hy-droxy-phen-yl)ethyl-idene]amino}-1-(2-methyl-phen-yl)thio-urea.

In the title thio-urea derivative, C(16)H(17)N(3)OS, the hy-droxy- and methyl-substituted benzene rings form dihedral angles of 9.62 (12) and 55.69 (6)°, respectively, with the central CN(3)S chromophore (r.m.s. deviation = 0.0117 Å). An intra-molecular O-H⋯N hydrogen bond ensures the coplanarity of the central atoms. The H atoms of the NH groups are syn and the conformation about the N=C double bond [1.295 (4) Å] is E. In the crystal, helical supra-molecular chains sustained primarily by N-H⋯S hydrogen bonds are found. Additional stabilization is provided by C-H⋯π and π-π [ring centroid(hy-droxy-benzene)⋯ring centroid(methyl-benzene) = 3.8524 (18) Å] inter-actions.

4-(3,4-Dimethyl-5-phenyl-1,3-oxazolidin-2-yl)-2-methoxy-phenol.

In the title compound, C(18)H(21)NO(3), the oxazolidine ring adopts an envelope conformation with the N atom at the flap position. The two benzene rings make dihedral angles of 74.27 (14) and 73.26 (15)° with the mean plane through the oxazolidine ring. In the crystal structure, O-H⋯O and C-H⋯O hydrogen bonds connect adjacent mol-ecules into chains along [010] incorporating R(2) (2)(8) loops and further stabilization is provided by weak inter-molecular C-H⋯π inter-actions.

2-Amino-4,6-dimethyl-pyridinium benzoate.

In the title compound, C(7)H(11)N(2) (+)·C(7)H(5)O(2) (-), the 2-amino-4,6-dimethyl-pyridinium cation and the benzoate anion are linked by two N-H⋯O hydrogen bonds, forming an R(2) (2)(8) ring motif. The H atoms in both the methyl groups are rotationally disordered, with fixed site occupancies of 0.50. In the crystal structure, the mol-ecules are stabilized by inter-molecular N-H⋯O hydrogen bonds. A π-π inter-action, with a centroid-centroid distance of 3.661 (2) Å, is also observed.