Molecular Docking, MM-GBSA, and Molecular Dynamics Approach: 5-MeO-DMT Analogues as Potential Antidepressants.

Since depression is a common mental illness affecting an estimated 5% of people worldwide, investigators are encouraged to develop effective antidepressants. According to the monoamine-deficiency hypothesis, the underlying pathophysiology of depression is a deficiency of some neurotransmitters (serotonin, norepinephrine, or dopamine) in the central nervous system. The neurotransmitter serotonin has drawn the most attention concerning depression. As per research, 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) elevates inter-synaptic serotonin levels when administered as a single inhalation of vapor from dried toad secretion and leads to higher life satisfaction, convergent thinking, higher ratings of mindfulness, lower ratings of depression, and anxiety. Furthermore, although 5-MeO-DMT lowers stress biomarkers such as cortisol, it is a psychedelic with hallucinogenic effects. In the present study, analogues of 5-MeO-DMT are designed with the hope that they might have better therapeutic activity and lower psychedelic side effects. The current study aimed to look at 5-MeO-DMT analogues as possible antidepressants. We used 70,000 5-MeO-DMT analogues that were sketched using Marvin to conduct a High Throughput Virtual Screening method in hopes of finding potential 5-MeO-DMT analogues against the 5-Hydroxytryptamine 1A receptor (5-HT1AR; 7E2Y.pdb) as an agonist. The prediction of the analogue-protein interaction and the evaluation of the binding affinity is accomplished by employing molecular docking. The Glide XP docking data indicated that a total of 21 compounds had Glide gscores ranging from -11.41 to -6.53 kcal/mol. When compared to the standard 5-MeO-DMT with the binding affinity of -7.75 kcal/mol, 14 compounds showed better binding affinity. Furthermore, Molecular Mechanics -Generalised Born and Surface Area solvation (MM-GBSA) indicated a binding free energy range of -63.55 to -35.37 kcal/mol, and 18 compounds showed better binding free energy than standard 5-MeO-DMT (-41.42 kcal/mol). Through ligand binding interactions with Asp116, Phe361, Phe362, Ser190, Ser199, Val117, Trp358, Ala365, Pro369, Ile189, Tyr195, Ala203, Ile167, Tyr390, Cys120, Trp358, Val364, Ala365, and Leu368, these complexes were stabilized, according to the molecular dynamic simulation of 20453/7E2Y in 100ns.

Enantiomeric Separation of Meclizine Hydrochloride in Pharmaceutical Dosage Form by HPLC Method.

OBJECTIVE: A basic, powerful and isocratic chiral fluid chromatographic technique was created and approved for the enantiomeric partition of meclizine hydrochloride in pharmaceutical dose structure. METHODS: The chromatographic partition was accomplished on Phenomenex® Lux Cellulose 1 (250 mm x 4.6 mm i.d, 5 µm molecule size) section utilizing portable stage framework containing acetonitrile: 25mM ammonium bicarbonate (75:25%v /v). The versatile stage was siphoned on the segment at the stream pace of 1.0 mL/min, and UV recognition was done at 230 nm. RESULT: The breaking points of recognition and measurement were observed to be 0.25 µg/mL and 1.00 µg/mL individually, for 20µL infusion volume. The alignment bend demonstrated phenomenal linearity over the focus scope of 1-5 µg/mL for (±) meclizine enantiomers with a relationship coefficient (r2 = 0.999). The recuperation investigation of meclizine from tablet plan was observed to be 97.33% and 98.81% separately. Meclizine standard arrangement and versatile stage were observed to be steady for in any event 32h. The meclizine enantiomers were very much settled with mean maintenance times of about (+) Meclizine at 13.14 min and (-) Meclizine at 14.33 min individually. CONCLUSION: The created technique was broadly approved and demonstrated to be hearty, exact, exact and appropriate for the examination of meclizine enantiomers in tablet measurement structure and security investigations of meclizine.

In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer.

BACKGROUND: Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. OBJECTIVE: Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. METHODS: Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. RESULTS: Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. CONCLUSION: The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.

Synthesis and characterization of some novel fatty acid analogues: a preliminary investigation on their activity against human lung carcinoma cell line.

BACKGROUND: Preparation of some novel heterocyclic compounds with long alkyl and alkenyl chain of cytotoxic activity. METHODS: Gamma linolenic acid, a poly unsaturated fatty acid and stearic acid, a saturated fatty acid were isolated from the microalga Spirulina platensis. Some novel gamma linolenic acid and stearic acid analogues having 1,3,4-oxadiazole and 1,2,4-triazole were synthesized and characterized by IR, 1H NMR, 13C NMR and mass spectral analysis. Cytotoxicity of these compounds was evaluated by the growth inhibition of A-549 cells in-vitro. RESULTS: Compound 1 and 3 showed comparable cytotoxicity against the human lung carcinoma A-549 cell lines.

Synthesis, antidepressant and antimicrobial activities of some novel stearic acid analogues.

Stearic acid, a saturated fatty acid was isolated from the microalga Spirulina platensis. Some novel stearic acid analogues having 1,3,4-oxadiazole, 1,2,4-triazole and 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole are synthesized and characterized by IR, NMR and mass spectral analysis. All the synthesized compounds were screened for antimicrobial activity by using cup plate method. The synthesized compounds have been further screened for their antidepressant activity in swiss albino mice by forced swim test (FST), midbrain dopamine has been estimated and quantified. All the compounds showed good antimicrobial activity and compound 6 showed significant antidepressant activity.

Synthesis and neuropharmacological evaluation of some novel quinoxaline 2, 3-dione derivatives.

Quinoxaline-2, 3-dione obtained from cyclocondensation reaction of o-phenylene diamine with oxalic acid was reacted with three different ketones and formaldehyde to give the corresponding Mannich bases in satisfactory yield. Their structures were confirmed by using (1)H NMR, IR, and mass analysis. In pharmacological evaluation, the synthesized compounds showed its curative effect against ethidium-bromide-induced demyelination in rats. For the purpose, different screening methods such as open field exploratory behavior test, rota rod test, grip strength test, beam walk test, and photo actometer test were performed. Ethidium bromide induction showed muscle weakness; muscle discoordination; loss of locomotor activity, and so forth, the synthesized drugs reversed all the above-mentioned neuromuscular disorders caused by ethidium bromide administration.

Synthesis and biological evaluation of some schiff bases of [4-(amino)-5-phenyl-4H-1, 2,4-triazole-3-thiol].

The basic nucleus 4-(amino)-5-phenyl-l-4H-1,2,4-triazole-3-thiol was prepared by cyclisation of potassium dithiocarbazinate with hydrazine hydrate using water as solvent under reflux condition for 3-4 h. The compound which has been synthesized successfully was subjected to addition reaction with different aldehydes to synthesize Schiff bases. The compounds were confirmed by physical parameters (solubility, melting point), chromatographic methods (TLC) and at last spectroscopic methods (IR, NMR, and Mass). In order to ascertain the pharmaceutical application, the selective pharmacological screening of the derivatives was carried out according to the standard procedures. The compounds were screened for their antianxietic activity by elevated plus maze method, antidepressant activity by forced swim test. Among the synthesized compounds, the Schiff bases of benzaldehyde (5e), furfuraldehyde (5d) and 2,4-dichloro benzaldehyde (5a) showed extremely significant activities. Results indicate that these compounds may be potential candidates for managing CNS disorders. However further studies are required to substantiate the same which are underway in our lab.