Letters in Drug Design & Discovery - Volume 18, Issue 6, 2021

Background: New N-substituted 5-(oxoindolinyl)-2-thioxo- thiazolidinone derivatives were synthesized. Materials and Methods: The C² -substituted thiazolidinone derivatives with piperidinyl and morpholinyl moieties in addition to the tetracyclic [(oxindolo)pyrazino]thiazolidine, the chloro- and aminoderivatives of the (indolyl)thiazolidinone ring system were also prepared. Results: The COX-2 inhibition activity of the synthesized compounds was investigated by studying their ability to inhibit the conversion of arachidonic acid to prostaglandin H2 (PGH2). Five of the tested candidates, substituted (oxonidolyl)thiazolidine derivatives (3a, 6f, 8b, 10 and 12) showed significant COX-2 inhibitory activity exhibiting IC50 values better than or close to the reference celecoxib. The anti-inflammatory activity was studied revealing that a number of compounds have shown good activities and compound 10 produced no significant mucosal injury. Conclusion: Molecular docking study was implemented to interpret the variable inhibitory activity of the newly synthesized compounds against COX enzyme. The results suggested that some of these derivatives could be active COX inhibitors possessing a high preference for COX-2.

Background: The ability of Pseudouridimycin (PUM) to occupy the nucleotide addition site of bacterial RNA Polymerase (RNAP) underlies its inhibitory potency, as previously reported. PUM has gained high research interest as a broad-spectrum nucleoside analog that has demonstrated exciting potentials in treating drug-resistant bacterial infections. Objective: Herein, we identified, for the first time, a novel complementary mechanism by which PUM elicits its inhibitory effects on bacterial RNAP. Materials and Methods: The dynamic binding behavior of PUM to bacterial RNAP was studied using various dynamic analysis approaches. Results: Findings revealed that in addition to occupying the nucleotide addition site, PUM also interrupts the unimpeded entry and exit of DNA by reducing the mechanistic extension of the RNAP cleft and perturbing the primary conformations of the switch regions. Moreover, PUM binding reduced the distances between key residues in the β and β’ subunits that extend to accommodate the DNA. Conclusion: This study’s findings present structural insights that would contribute to the structure-based design of potent and selective PUM inhibitors.

Background: The breast cancer takes the first place among women cancer diagnosed worldwide. Objective: Based on the preferential multi-targeted approach to cancer therapy, we, in this study, aimed to design in silico drug candidates possessing multi-targeted bioactivity to cope with multidrug resistance using the known drug structures, molecular modeling, and ADME parameters. Materials and Methods: We first evaluated the bioactivity score of the approved breast cancer drugs across the top-three drug targets GPCR, kinase, and nuclear receptors and calculated their physicochemical properties to see their drug-likeness profiles. Among 29 approved drugs, Aromasin and Capecitabine showed the broadest bioactivity across the targets listed. By using molecular modeling and bioisosteric modifications, and applying two filtering approaches, we investigated thirty-one analogues of Aromasin and Capecitabine. Results: Software prediction resulted in that the compounds A14, C4, and C13 replaced with B(OH)2 and/or Si(CH3)3 showed a broader spectrum of biological activity with a multi-targeted manner than even the approved analogs. Conclusion: The interesting point of these new design molecules is to have either silicon and/or boron incorporation. The increased bioactivity effect of Silicon and Boron incorporation is also seen in the recently approved drug list of FDA and in clinical trials ongoing. Our new design boron and silicon-based molecules appeared to be promising candidates for breast cancer treatment to be tested in vitro, in vivo, and in the clinic for further pharmacological investigations.

Background: Recently, Coronavirus Disease-2019 (COVID-19), caused by a fatal strain of coronavirus named Severe Acute Respiratory Syndrome-2 (SARS-CoV-2), has been declared as a pandemic by the World Health Organisation (WHO) on 11 March 2020. Globally, no therapy such as vaccines and specific therapeutic agents is available so far despite some protease inhibitors and antiviral agents. Introduction: Due to no therapeutic drug or vaccine against SARS-CoV-2 so far, phytomedicine may be developed as therapeutic agents in the prevention and treatment of current COVID-19 disease. Thus, the aim of this study was to find out a suitable therapeutic agent from selected 17 dietary molecules, which could target SARS-CoV-2 encoded proteins. Materials and Methods: In this study, 3D structures of selected dietary molecules were obtained from the PubChem database, which have previously been reported for their antiviral and anti-inflammatory effects. Then, molecular docking analysis by using AutoDoc4 and AutoDockVina software was conducted to evaluate their anti-SARS-CoV-2 activity. Lipinski’s rule of five and drug-likeness properties were also discussed with the help of Molinspiration and the OSIRIS property explorer methods. Results: Our results revealed that, among all, epigallocatechin gallate (EGCG) (7) is a lead compound that could fit well into the binding sites of docked proteins of SARS-CoV-2. EGCG showed very strong molecular interactions with the free enzyme of main protease (6y2e), chimeric receptorbinding domain complexed with human ACE2 (6vw1), and NSP15 endoribonuclease (6vww) encoded proteins of SARS-CoV-2, by showing binding energies -9.30, -8.66, and -8.38, kcal/mole, respectively. Conclusion: In the present study, EGCG (7) is more active than two standard drugs that are currently being used in COVID 19, namely remdesivir and nafamostat. Therefore, EGCG (7), as per our results, might be explored as a therapeutic agent for the treatment of COVID-19.

Background: Diabetes mellitus is a challengeable metabolic disorder that leads to a group of complications when the HbA1c level is not maintained. Most of the existing drugs available in the market in long-term use may lead to serious adverse effects. Hence, current research focuses on drug development for the management of diabetes by synthesizing natural mimicking flavonoid analogues. Objective: This study focused on the synthesis of flavanone derivatives imitating natural flavonoid core and investigated for their antidiabetic and antioxidant activity, which can help in the development of drug discovery targeting diabetic management. Materials and Methods: The novel 2-phenyl-2,3-dihydro-chromen-4-ones were synthesized from 1,3-diphenyl-prop-2-en-1-one derivatives and characterized using UV, IR, ¹HNMR, ¹³CNMR and mass spectroscopic techniques. Drug target site was determined using graph theoretical analysis and screened the characterized title compounds for their in-silico studies by analyzing their physiochemical properties, ADMET studies, and molecular docking analysis. Antidiabetic and free radical scavenging effects were investigated both by in-vitro (alpha-amylase inhibitory assay) and in-vivo models. Streptozotocin (STZ) induced rats were used as in-vivo models. Results: The α-amylase inhibitory assay showed flavanones with hydroxyl substitution HFA1- HFA7 had significant IC50 values. The test compounds (HFA3-HFA7) were investigated for their antidiabetic activity on STZ induced rats at 40 mg/kg. The blood glucose level and antioxidant enzymes were significantly restored by title compounds (HFA5, HFA4, and HFA6) with an electron-donating group such as hydroxyl, methoxy and thiophenyl group on ring B compared to glibenclamide. Conclusion: These results suggest that naturally mimicking synthesized flavanone have antidiabetic and antioxidant properties, which can aid in the development of drugs towards diabetes management.

Background: Inflammatory diseases are one of the major concerns of today’s world; major disorders caused by inflammation include, allergy, asthma, arthritis, hepatitis, autoimmune diseases, celiac disease, etc. During most of these events, many proteins and molecules expression are modulated and one such protein is AP-1 (c-Fos-c-Jun heterodimer complex). AP-1 is a dimeric protein activated by several physiological stimuli and environmental insults such as growth factors, polypeptide hormones, neurotransmitters, cytokines, cell-matrix interactions, UV irradiations, viral and bacterial infections. Objective: Present study is mainly focused on designing small molecule analogs to inhibit the c- Fos-c-Jun complex, as the complex is involved in many inflammatory diseases and precisely involved in disease progression. Therefore, it had been considered as a therapeutic target for more than a decade. Materials and Methods: In the present study, an attempt was made to design the analogs of referral drug T-5224. 31 analogs of T-5224 were designed by chemoinformatics approach and subjected to ADMETox for screening. Results: Among the 16 compounds that were found to pass the evaluation, all 16 compounds passed the toxicity evaluation except the 7th molecule. The molecular docking study showed that compounds 1, 2 and 16 had high inhibition constant. Conclusion: The preliminary results suggest the compounds 1, 2 and 16 have the potential ligand binding capacity with the cFos-cJun complex. Further analysis, with advanced tools, may result in potential small molecules to inhibit the c-Fos-c-Jun complex.

Background: The rapid spread of SARS-CoV-2 has caused havoc and panic among individuals, which has further worsened due to the unavailability of a proven drug(s) regime. Objective: The current work involves drug repurposing from the pool of USFDA approved drugs involving in silico virtual screening technique against COVID-19. Materials and Methods: Methodology involves virtual screening of 8548 FDA approved drugs against target protein endoribonuclease NendoU (Nsp15) (PDB ID: 6VWW). Result: Virtual screening-based analysis enabled us to identify four drugs, Eprosartan, Inarigivir soproxil, Foretinib, and DB01813 that could plausibly target Nsp15 against COVID-19 disease. Conclusion: The work offers the scope to corroborate the findings via in vitro and in vivo techniques to identify the potential of selected leads against COVID-19. The outcome may also help in tracing their molecular mechanism(s) in addition to their development at the clinical level in the future.

Background: Since time immemorial, the ethnic community of Mayrubhanj District, Odisha, India has preferred Olecophylla smaragdina as traditional medicine for their multiple ailments. Hence, the objective of this investigation is to scientifically examine the myth behind ethno-zoological claims using chemometric analysis as well as in vitro and in silico study. Materials and Methods: The maceration method was used for the extraction of O. smaragdina using hexane and methanol. In this study, various bioactive compounds of O. smaragdina were identified through GC-MS analysis followed by an antimicrobial activity. The species were further studied for their binding modes for in silico inhibition of a choice of bacterial proteins using Biovia Discovery studio software. Results: Tetradecanoic acid, hexadecanoic acid, methyl ester, hexadecenoic acid, n-hexadecanoic acid, 9-octadecenoic acid, methyl ester, oleic acid and 9-octadecenamide are some important bioactive constituents identified through GCMS analysis. The hexane extract was found to have maximum inhibitory activity against Staphyllococus aureus. The inhibitory activity of hexane and methanolic extract against S. aureus at a concentration of 400 μg/mL was found to be 90% and 83%, respectively. The high inhibitory capacity of the n-hexane extract was comparable to the standard drug Gentamycin which further supported the high receptor binding affinity of the identified compound Octadecanoic acid towards Tyrosol-t RNA synthetase of staphylococcus aureus (PDB ID: 1JIK). Conclusion: Interestingly, this is probably the first report that obtained bioactive molecules from O. smaragdina showing the binding site identification to carry out molecular docking studies, and better affinity to bind with suitable targeted moiety.