Advancement of Computational Design Drug Delivery System in COVID-19: Current Updates and Future Crosstalk- A Critical update.

Positive strides have been achieved in developing vaccines to combat the coronavirus-2019 infection (COVID-19) pandemic. Still, the outline of variations, particularly the most current delta divergent, has posed significant health encounters for people. Therefore, developing strong treatment strategies, such as an anti-COVID-19 medicine plan, may help deal with the pandemic more effectively. During the COVID-19 pandemic, some drug design techniques were effectively used to develop and substantiate relevant critical medications. Extensive research, both experimental and computational, has been dedicated to comprehending and characterizing the devastating COVID-19 disease. The urgency of the situation has led to the publication of over 130,000 COVID-19-related research papers in peer-reviewed journals and preprint servers. A significant focus of these efforts has been the identification of novel drug candidates and the repurposing of existing drugs to combat the virus. Many projects have utilized computational or computer-aided approaches to facilitate their studies. In this overview, we will explore the key computational methods and their applications in the discovery of small-molecule therapeutics for COVID-19, as reported in the research literature. We believe that the true effectiveness of computational tools lies in their ability to provide actionable and experimentally testable hypotheses, which in turn facilitate the discovery of new drugs and combinations thereof. Additionally, we recognize that open science and the rapid sharing of research findings are vital in expediting the development of much-needed therapeutics for COVID-19.

One-Pot Synthesis of Novel Hydrazono-1,3-Thiazolidin-4-One Derivatives as Anti-HIV and Anti-Tubercular Agents: Synthesis, Biological Evaluation, Molecular Modelling and Admet Studies.

BACKGROUND: The necessity for newer anti-HIV and anti-tubercular medications has arisen as a result of the prevalence of opportunistic infections caused by HIV (human immunodeficiency virus). OBJECTIVE: A series of ten new hydrazono 1,3-thiazolidin-4-one derivatives were synthesized in one-pot and evaluated for anti-HIV and anti-tubercular activities. Molecular Docking was accomplished with HIV-1 reverse transcriptase protein (PDB ID: 1REV) and Mycobacterium Tuberculosis (M. tuberculosis) H37Rv protein (PDB ID: 2YES) receptors along with drug-likeness and ADMET properties. METHODS: One-pot synthesis of hydrazono 1,3-thiazolidin-4-one derivatives was carried out by ketones, thiosemicarbazide and ethylchloroacetate with the catalyst of anhydrous sodium acetate. All the synthesized compounds were characterized and evaluated for their in-vitro anti-HIV and also evaluated for their in-vitro anti-tubercular activity against M. tuberculosis H37Rv. In-silico predicted physicochemical parameters were done by MedChem DesignerTM software version 5.5 and ADMET parameters by pkCSM online tool. Furthermore, molecular docking was performed with pyrx 0.8 by autodock vina software. RESULTS: All the synthesized compounds were characterized and evaluated for their in-vitro anti- HIV activity for inhibition of syncytia formation, which shows KTE1 with EC50 47.95 µM and Selectivity Index (SI) of >4.17 and for inhibition of p24 antigen production EC50 was found to be 80.02 µM and SI of >2.49. The compounds were also evaluated for their in-vitro anti-tubercular activity against M. tuberculosis H37Rv, in which KTE1 MIC values of 12.5µg/ml with SI of >4.0 and cytotoxicity against Vero cell lines. In-silico predicted physicochemical parameters for synthesized compounds which were found to be drug-like. Furthermore, docking has shown a good dock score and binding energy with anti-HIV and anti-tubercular receptors. CONCLUSION: From the novel synthesized molecules, none of the molecule is as effective as standards for anti-HIV and anti-tubercular drugs and hence can be further explored for its potential activities. Furthermore, derivatization was made to achieve more potent compounds for anti-HIV and anti-tubercular drugs.

A Novel Ultra Performance Liquid Chromatography-PDA Method Development and Validation for Darunavir in Bulk and Its Application to Marketed Dosage Form.

AIMS AND OBJECTIVE: The aim of this study was to develop and validate a novel ultra-performance liquid chromatographic method for estimation of darunavir in a bulk and tablet dosage form. MATERIALS AND METHODS: The chromatographic separation was achieved using DIKMA Endoversil (2.1mm x 50mm, 1.7 µm) column. A mixture of 40% buffer (0.1% octa sulfonic acid) and 60% acetonitrile was used as a mobile phase with the isocratic elution mode and eluent was monitored at 281nm using UV detector. The method was continued and validated in accordance with International Conference on Harmonization Guidelines. Validation study revealed the specificity and reliability of the method. RESULTS: In this method, darunavir was eluted with retention time of 0.516 min. Calibration curve plots were found linear over the concentration ranges 10-50 µg/mL for darunavir. Limit of detection was 0.02 µg/mL and limit of quantification was found 0.07 µg/mL. The present method was also found stable in force degradation study. CONCLUSION: The empirical evidences of all the study results revealed the suitability of the estimation of darunavir in bulk and tablet dosage form without any interference from the excipients.

Synthesis of Novel Aryl (4-Aryl-1H-Pyrrol-3-yl) (Thiophen-2-yl) Methanone Derivatives: Molecular Modelling, In Silico ADMET, Anti-Inflammatory and Anti-Ulcer Activities.

BACKGROUND: Due to the presence of both five-membered heterocyclics like pyrrole and thiophene in one molecule considerable attention was made for their enormous pharmacological activities out of which include anti-inflammatory and anti-ulcer activities. OBJECTIVE: Chalcones with toluenesulfonylmethyl isocyanide (TosMIC) undergo synthesis to form some new aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives. Molecular docking of synthesized compounds with protein receptors of anti-inflammatory COX-1(3N8Y), COX-2 (1PXX) along with anti-ulcer H+/K+ATPase enzyme (2XZB) followed with drug-likeness, and in silico ADMET properties. MATERIALS AND METHODS: The multicomponent reaction was carried out by the intermediate formation of α, ß-unsaturated ketone from carbonyl compounds which on sequential addition undergoes [3+2] cycloaddition reaction in same medium affords aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives by addition of TosMIC in basic medium had resulted in series of compounds PY1 to PY12. All the new synthesized compounds were screened for their in-vitro anti-inflammatory activity by bovine serum albumin method followe with COX assay, and in-vivo by using carrageenan-induced rat paw edema method of the selected compounds PY1, PY5 and PY12 which is also screened for anti-ulcer activity by pylorus ligation method, respectively. Molecular docking was performed using autodock tools, drug-likeness by OSIRIS property explorer and admetSAR properties. RESULTS AND DISCUSSION: From the synthesized compounds of aryl (4-aryl-1H-pyrrol-3-yl) (thiophen- 2-yl) methanone derivatives PY5 showed decent in-vitro and in-vivo anti-inflammatory along selectivity index of 6.2 for COX-1 with IC50(µM) value of 9.54 over diclofenac with 8.74 and PY1 showed decent in-vivo anti-ulcer activities along with drug-likeness and in silico ADMET predictions revealed that all the synthesized compounds have minimal toxic effects with good absorption as well as solubility characteristics. The selected compounds may serve as potential lead compounds for developing new anti-inflammatory and anti-ulcer drugs. CONCLUSION: From the newly synthesized molecules PY5 was found to be effective for anti-inflammatory and PY1 was found to be effective for anti-ulcer activities further derivitization and designed of modification to achieve more compounds with potent anti-inflammatory and anti-ulcer activities.

Hepatoprotective activity of Macrothelypteris torresiana (Gaudich.) aerial parts against CCl4-induced hepatotoxicity in rodents and analysis of polyphenolic compounds by HPTLC.

Macrothelypteris torresiana is a fern species belonging to family Thelypteridaceae. The present study was conducted to evaluate hepatoprotective potential of ethanol extract from M. torresiana aerial parts (EEMTAP) and detect the polyphenolic compounds present in the extract using high performance thin layer chromatography (HPTLC). Hepatoprotective potential of EEMTAP were tested at doses of 300 and 600 mg/kg, per os (p.o.), on Wistar albino rats. The extract and silymarin treated animal groups showed significant decrease in activities of different biochemical parameters like serum glutamic oxaloacetic transaminase (SGOT), serum glutamate-pyruvate transaminase (SGPT), alkaline phosphatase (ALP), which were elevated by carbon tetrachloride (CCl4) intoxication. The levels of total bilirubin and total protein alongwith the liver weight were also restored to normalcy by EEMTAP and silymarin treatment. After CCl4 administration the level of hepatic antioxidant enzymes such as Glutathione (GSH) and Catalase (CAT) were decreased whereas the level of hepatic lipid peroxidation (LPO) was elevated. The level of these hepatic antioxidant enzymes were also brought to normalcy by EEMTAP and silymarin treatment. Histological studies supported the biochemical findings and treatment with EEMTAP at doses 300 and 600 mg/kg, p.o. was found to be effective in restoring CCl4-induced hepatotoxicity in rats. A simple HPTLC analysis was conducted for the detection of polyphenolic compounds in EEMTAP, and the result revealed the presence of caffeic acid as phenolic acid and quercetin as flavonoid. The proposed HPTLC method is simple, concise and provides a good resolution of caffeic acid and quercetin from other constituents present in EEMTAP.

A Complete Profile on Blind-your-eye Mangrove Excoecaria Agallocha L. (Euphorbiaceae): Ethnobotany, Phytochemistry, and Pharmacological Aspects.

Traditional system of medicine consists of large number of plants with various medicinal and pharmacological importances. This article provides a comprehensive review of the complete profile of an important mangrove plant Excoecaria agallocha L. (Euphorbiaceae) and elaborately describing the ethnobotany, phytochemistry, and pharmacological properties. It is used traditionally in the treatment of various diseases such as epilepsy, ulcers, leprosy, rheumatism, and paralysis. The latex obtained from the bark is poisonous in nature and may cause temporary blindness, thus it is also known as the blind-your-eye mangrove plant. Many phytoconstituents were isolated from the plant, which were mainly diterpenoids, triterpenoids, flavonoids, sterols, and few other compounds. The plant also showed many pharmacological activities such as antioxidant, antimicrobial, anti-inflammatory, analgesic, antiulcer, anticancer, antireverse transcriptase, antihistamine-release, antifilarial, DNA damage protective, antidiabetic, and antitumor protecting activities. Hence, this review could help guide researchers anticipating to undertake further investigations in these directions.

Analgesic, anti-inflammatory and antipyretic activities of the ethanolic extract and its fractions of Cleome rutidosperma.

Oral administration of the ethanolic extract (200 and 400 mg/kg, p.o) and its fractions (200 mg/kg each) of the aerial parts of Cleome rutidosperma produced significant analgesic activity in acetic acid-induced writhing and tail immersion tests, anti-inflammatory effect against carrageenin induced inflammation and adjuvant induced polyarthritis and antipyretic activity against yeast-induced pyrexia. Fractionation of the ethanolic extract potentiated the activities.