Exploring nature’s bounty: identification ofWithania somniferaas a promising source of therapeutic agents against COVID-19 by virtual screening andin silicoevaluation

Article

Author: Srivastava, A. N. ; Siddiqui, Sahabjada ; Srivastava, Aditi ; Ahmad, Rumana ; Ahmad, Bilal ; Mehrotra, Sudhir

Coronaviruses are etiological agents of extreme human and animal infection resulting in abnormalities primarily in the respiratory tract. Presently, there is no defined COVID-19 intervention and clinical trials of prospective therapeutic agents are still in the nascent stage. Withania somnifera (L.) Dunal (WS), is an important medicinal plant in Ayurveda. The present study aimed to evaluate the antiviral potential of selected WS phytoconstituents against the novel SARS-CoV-2 target proteins and human ACE2 receptor using in silico methods. Most of the phytoconstituents displayed good absorption and transport kinetics and were also found to display no associated mutagenic or adverse effect(s). Molecular docking analyses revealed that most of the WS phytoconstituents exhibited potent binding to human ACE2 receptor, SAR-CoV and SARS-CoV-2 spike glycoproteins as well as the two main SARS-CoV-2 proteases. Most of the phytoconstituents were predicted to undergo Phase-I metabolism prior to excretion. All phytoconstituents had favorable bioactivity scores with respect to various receptor proteins and target enzymes. SAR analysis revealed that the number of oxygen atoms in the withanolide backbone and structural rearrangements were crucial for effective binding. Molecular simulation analyses of SARS-CoV-2 spike protein and papain-like protease with Withanolides A and B, respectively, displayed a stability profile at 300 K and constant RMSDs of protein side chains and Cα atoms throughout the simulation run time. In a nutshell, WS phytoconstituents warrant further investigations in vitro and in vivo to unravel their molecular mechanism(s) and modes of action for their future development as novel antiviral agents against COVID-19.

01 Jun 2020·BioinformaticsQ3 · BIOLOGY

Potential covalent drugs targeting the main protease of the SARS-CoV-2 coronavirus

Q3 · BIOLOGY

Article

Author: Wang, Zhiying ; Zheng, Qiang ; Liu, Sen

AbstractMotivationSince December 2019, the newly identified coronavirus SARS-CoV-2 has caused a massive health crisis worldwide and resulted in over 70 000 COVID-19 infections so far. Clinical drugs targeting SARS-CoV-2 are urgently needed to decrease the high fatality rate of confirmed COVID-19 patients. Traditional de novo drug discovery needs more than 10 years, so drug repurposing seems the best option currently to find potential drugs for treating COVID-19.ResultsCompared with traditional non-covalent drugs, covalent drugs have attracted escalating attention recent years due to their advantages in potential specificity upon careful design, efficiency and patient burden. We recently developed a computational protocol named as SCAR (steric-clashes alleviating receptors) for discovering covalent drugs. In this work, we used the SCAR protocol to identify possible covalent drugs (approved or clinically tested) targeting the main protease (3CLpro) of SARS-CoV-2. We identified 11 potential hits, among which at least six hits were exclusively enriched by the SCAR protocol. Since the preclinical or clinical information of these identified drugs is already available, they might be ready for being clinically tested in the treatment of COVID-19.Contactsenliu.ctgu@gmail.com

01 Jan 1998·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Studies on Agents with Vasodilator and .BETA.-Blocking Activities. V. Synthesis and Pharmacological Activity of the Optical Isomers of TZC-5665.

Q4 · MEDICINE

Article

Author: Miyazawa, Katuhiko ; Nakao, Tomio ; Seki, Toshimi ; Shibata, Kenyu ; Asano, Hajime ; Shiraiwa, Masahumi ; Kanada, Arihiro ; Yasuda, Kikuo ; Ishimori, Tsutomu ; Minami, Nobuyoshi

Synthesis of the four optical isomers of TZC-5665 (1), a candidate for the treatment of congestive heart failure, was achieved by the reaction of chiral diaminopyridazinone (2) with chiral glycidyl ether. (3). The hypotensive and beta-blocking activities of 1 and its optical isomers were examined when given intravenously into anesthetized rats. Furthermore these compounds were evaluated for inhibitory activity on cAMP phosphodiesterase III. Among the four optical isomers, Ra,Sb-one (1c) possessed the essential activities of TZC-5665 (1).

100 Deals associated with Oberadilol Monoethyl Maleate

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Phase 2	-	ASKA Pharmaceutical Co., Ltd.	-
Heart Failure	Phase 2	Japan	Teikoku Hormone Manufacturing Co., Ltd.	-
Hypertension	Phase 2	Japan	Teikoku Hormone Manufacturing Co., Ltd.	-

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