New pandemic infection of coronaviridae family virus spread to more than 210 countries with total infection of 1,136,851 and 62,955 (4.6%) deaths until 5th April 2020. Which stopped the regular cycle of humankind but the nature is consistently running. There is no micro molecule remedy found yet to restore the regular life of people. Hence, we decided to work on natural biophores against the COVID proteins. As a first step, major phytoconstituents of antiviral herbs like Leucas aspera, Morinda citrifolia, Azadirachta indica, Curcuma longa, Piper nigrum, Ocimum tenuiflorum, and Corallium rubrum collected and performed the lock and key analysis with major spike protein of COVID-19 to find the best fitting lead biophore using computational drug design platform. The results of protocol run showed, phytoconstituents of Morinda citrifolia and Leucas aspera were found lower binding energy range of − 55.18 to − 25.34 kcal/mol, respectively and compared with Hydroxychloroquine (HCQ) (− 24.29 kcal/mol) and Remdesivir (− 25.38 kcal/mol). The results conclude that, core skeletons chromen, anthracene 9, 11 dione and long-chain alkyl acids/ester-containing biophores showen high stable antagonistic affinity with S-protein. Which leads the breakdown of spike protein and ACE2 receptor complex formation and host mechanism of corono virus. In addition, the dynamic trajectory analysis confirmed the complete denaturation of spike protein by the molecule 4-(24-hydroxy-1-oxo-5-n-propyltetracosanyl)-phenol from Leucas aspera and stability of spike-ligand complex. These biophores will aid the researcher to fabricate new promising analogue and being recommended to assess its COVID-19 treatment.

Fluoroquinolones (FQs) belong to the class of quinolone drugs that are used to treat Urinary tract infections (UTIs) through inhibition of E. coli DNA gyrase. Resistance to FQs poses a serious problem in the treatment against resistant strains of E. coli which are associated with Ser83 to Leu and Asp87 to Asn mutations at the quinolone resistance determining region (QRDR) of the GyrA subunit of DNA gyrase. Mutant DNA GyrA (mtDNA GyrA) is deemed to be a significant target for the development of novel FQ drugs. Due to resistance to FQ drugs, discovery or development of novel FQs is crucial to inhibit the mtDNA GyrA. Hence, the present study attempts to design and develop novel FQs that are efficient against resistant E. coli strains. A three-dimensional structure of the mtDNA GyrA protein was developed by homology modeling, following which 204 novel FQ analogs were designed using target based SAR. The designed ligands were then screened using molecular docking studies, through which the pattern of interaction between the ligands and the target protein was studied. As expected, the results of the docking study revealed that the molecules FQ-147, FQ-151 and FQ-37 formed hydrogen bonding and Van der Waals interactions with Leu83 and Asn87 (mutated residues), respectively. Further, the wild-type (WT), mtDNA GyrA and docking complex were studied by molecular dynamics (MD) simulations. Subsequently, all the screened compounds were subjected to a structure and ligand based pharmacophore study followed by ADMET and toxicity (TOPKAT) prediction. Finally, eighteen hit FQ analogs which showed good results for the following properties, viz., best binding score, estimated activity (MIC value) and calculated drug-like properties, and least toxicity, were shortlisted and identified as potential leads to treat UTI caused by FQ resistant E. coli. Apart from development of novel drug candidates for inhibition of mtDNA GyrA, the present study also contributes towards a superior comprehension of the interaction pattern of ligands in the target protein. To a more extensive degree, the present work will be useful for the rational design of novel and potent drugs for UTIs.

The liver function test is an imperative element in chemotherapy management due to the idiosyncratic reaction of chemotherapy drugs. This study primly aimed to replace the toxic fragments of known protein tyrosine kinases inhibitors (PTKi) to develop safe and effective chemotherapy. All the current PTKi’s were docked with the tyrosine kinases and metabolic enzymes to study the affinities on the target. It resulted from most of the PTKi’s found higher affinity and efficacy with metabolic enzymes lead the hepatic cells damage. To overcome this limitation of PTKi’s, a bioisosteric replacement strategy was achieved and conceptual analogs were designed. Specifically, the Generated pose of the Axitinib molecule showed that axitinib fragments C = C-, -C = O and NH₂ produced clashes with active site residues of tyrosine kinases protein and good affinity with metabolic enzyme primes to the liver toxicity. The above said fragments were replaced with various bioisosteric groups and efficacy was measured. The resulting molecule shows improved affinity with tyrosine kinases enzyme and less interactions with metabolic enzyme were imminent molecule for the treatment of malignant cells with outside effects. Communicated by Ramaswamy H. Sarma

Methicillin-resistant Staphylococcus aureus (MRSA) infections are increasingly causing morbidity and mortality; thus, drugs with multifunctional efficacy against MRSA are needed. We extracted a novel compound from the halophilic Pseudomonas aeruginosa using an ethyl acetate (HPAEtOAcE). followed by purification and structure elucidation through HPLC, LCMS, and ¹H and ¹³C NMR, revealing the novel 5-(1H-indol-3-yl)-4-pentyl-1,3-oxazole-2-carboxylic acid (Compound 1). Molecular docking of the compound against the MRSA PS (pantothenate synthetase) protein was confirmed using the CDOCKER algorithm in BDS software with specific binding to the amino acids Arg (B:188) and Lys (B:150) through covalent hydrogen bonding. Molecular dynamic simulation of RMSD revealed that the compound–protein complex was stabilized. The proficient bioactivities against MRSA were attained by the HPAEtOAcE, including MIC and MBCs, which were 0.64 and 1.24 µg/mL, respectively; 100% biomass inhibition and 99.84% biofilm inhibition were observed with decayed effects by CLSM and SEM at 48 h. The hla, IrgA, and SpA MRSA genes were downregulated in RT-PCR. Non-hemolytic and antioxidant potential in the DPPH assay were observed at 10 mg/mL and IC₅₀ 29.75 ± 0.38 by the HPAEtOAcE. In vitro growth inhibition assays on MRSA were strongly supported by in silico molecular docking; Lipinski’s rule on drug-likeness and ADMET toxicity prediction indicated the nontoxic nature of compound.

Fluoroquinolones (FQs) are one of the most commonly prescribed classes of antibiotics for the treatment of urinary tract infections (UTIs), but FQ-resistant Escherichia coli (E. coli) in UTIs is widespread and increasing. In order to address the resistance-related issue, novel drug molecules with the capacity to overcome E. coli resistance are crucial for modern healthcare. Based on this rationale, the virtually screened novel FQ analogs FQ-49, FQ-70, FQ-131, FQ-132, FQ-137, FQ-147, FQ-151, FQ-172, FQ-177, and FQ-182 were synthesized using a microwave-assisted technique. These compounds possessed excellent activity against FQ-resistant E. coli and inhibited purified mutant DNA gyrase activity in vitro. A 3D-QSAR modeling study was used to identify the potent FQ analogs and calculate their molecular properties. Sequence analysis of the quinolone-resistance determining region (QRDR) of purified mutant DNA gyrase enzyme confirmed the presence of Ser83Leu and Asp87Asn mutations in FQ-resistant E. coli isolates from UTI patients. Overall, this study confirmed that ten of the synthesized novel FQ analogs exhibited extremely potent antibacterial activity against existing FQ-resistant E. coli, and they could be further successfully utilized for the treatment of UTIs.