Bioisosteric replacements of tyrosine kinases inhibitors to make potent and safe chemotherapy against malignant cells.

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.

Virtually screened novel sulfathiazole derivatives as a potential drug candidate for methicillin-resistant Staphylococcus aureus and multidrug-resistant tuberculosis.

Methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant tuberculosis (MDR-TB) is a leading cause of severe hospital and infection-related morbidity and mortality in the general population. There is a critical need for dynamic, powerful medication candidates to combat MRSA and MDR-TB infections in this specific setting. As a result, the current research focuses on the development of novel sulfathiazole derivative compounds that could be used as anti-MRSA and anti-MDR-TB agents. Virtual screening approaches were used to identify the potential lead sulfathiazole derivatives with the help of BIOVIA Discovery Studio 2017 software. In this in silico study, 10 novel sulfathiazole derivatives were virtually screened from 74 designed compounds. These 10 compounds had the best predictive docking scores in MRSA and MDR-TB receptors and were then put through a molecular dynamics simulation to explain protein stability, ligand characteristics and protein-ligand interactions. The Lipinski rule and ADMET prediction results also suggested that 11 compounds (mol-12, mol-22, mol-23, mol-28, mol-30, mol-32, mol-34, mol-35, mol-45 and mol-47) have strong drug similarity features. Our findings imply that the 10 novel sulfathiazole compounds studied could be viable new therapeutic leads for MRSA and MDR-TB.

Communicated by Ramaswamy H. Sarma.

Design and virtual screening of novel fluoroquinolone analogs as effective mutant DNA GyrA inhibitors against urinary tract infection-causing fluoroquinolone resistant Escherichia coli.

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.