Streptomyces smyrnaeus UKAQ_23, isolated from the mangrove-sediment, collected from Jubail,Saudi Arabia, exhibited substantial antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), including non-MRSA Gram-positive test bacteria. The novel isolate, under laboratory-scale conditions, produced the highest yield (561.3 ± 0.3 mg/kg fermented agar) of antimicrobial compounds in modified ISP-4 agar at pH 6.5, temperature 35 °C, inoculum 5% v/w, agar 1.5% w/v, and an incubation period of 7 days. The two major compounds, K1 and K2, were isolated from fermented medium and identified as Actinomycin X2 and Actinomycin D, respectively, based on their structural analysis. The antimicrobial screening showed that Actinomycin X2 had the highest antimicrobial activity compared to Actinomycin D, and the actinomycins-mixture (X2:D, 1:1, w/w) against MRSA and non-MRSA Gram-positive test bacteria, at 5 µg/disc concentrations. The MIC of Actinomycin X2 ranged from 1.56–12.5 µg/ml for non-MRSA and 3.125–12.5 µg/ml for MRSA test bacteria. An in-silico molecular docking demonstrated isoleucyl tRNA synthetase as the most-favored antimicrobial protein target for both actinomycins, X2 and D, while the penicillin-binding protein-1a, was the least-favorable target-protein. In conclusion, Streptomyces smyrnaeus UKAQ_23 emerged as a promising source of Actinomycin X2 with the potential to be scaled up for industrial production, which could benefit the pharmaceutical industry.

Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPβ1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing −5.30 kcal/mol and −84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting −6.9 kcal/mol and −66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs. Communicated by Ramaswamy H. Sarma

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Antiepileptic Antiosteoporotic Antioxidant Cardiovascular disease Circardian rhythm Hypnotic Immunodulatory Melatonin a b s t r a c t Melatonin is one of the most versatile and ubiquitous molecule widely distributed in nature has been reported to play a role in a wide variety of physiological responses including reproduction, circadian homeostasis, sleep, retinal neuromodulation, and vasomotor responses. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light ⁄ dark cycle via the suprachiasmatic nucleus. Melatonin is synthesized in all areas of the body such as gastrointestinal tract, skin, bone marrow, retina and in lymphocytes, from which it may influence other physiological functions through paracrine signalling. In addition to regulation of circadian rhythm of melatonin a variety of other physiological effects such as hypnotic, antidepressant, antiepileptic, oncostatic, immunomodulatory, antiosteoporotic, in cardiovascular disease, neuromodulatory and cerebral ischaemic condition have been reported.Moreover there is scarcity of literature that reviewed the scientific evidence for its use in these conditions. Therefore in this article we review recent advances in this research field, which is preceded by a concise account of general information about melatonin, melatonin receptors and intracellular signalling pathways for melatonin actions.

Melatonin is a pineal neurohormone whose secretion is influenced by circadian changes of 24 hour night and day cycle. Over the recent past, several studies have highlighted the ubiquitous influence of the circadian timing in almost all the physiologic functions. An altered/ deficient sleep-wake cycle has been correlated with physiological imbalances which are linked to the development of various disorders, viz depression, anxiety, psychosis, attention deficits, sleep deprivation and others. Melatonin and its oxidation products, viz cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykinuramine and N1-acetyl-5methoxykinuramine possess excellent antioxidant properties. Melatonin's beneficial neuroprotective properties are mostly attributed to excellent free radical scavenging properties. A gathering body of evidence has shown that besides strong antioxidant activities, melatonin is a pleiotropic regulator molecule which orchestrates multiple functions through all the three melatonin receptors, i.e. MT1, MT2, and MT3. For example, MT2 receptor agonistic activity is attributed to neuroprotective, hypnotic and anxiolytic properties while MT1 and MT2 agonistic activity is associated with the clinical efficacy of agomelatine. The third melatonin receptor has been identified as quinone reductase (QR) 2, an enzyme involved in detoxification. MT3 agonist has been linked to strong hypotensive effects in preclinical study.In conclusion, the gathering body of evidence both from preclinical and clinical literatures suggests strong antioxidant activities and diverse pleiotropic mechanisms of melatonin for potential neuroprotective role in diverse neuropsychiatric disorders. However, there is still a lack of melatonergic ligands with high selectivity and specificity to precisely target any particular neuropsychiatric disorders for which limited therapeutic options are currently available clinically.