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AbstractBacterial infections are rising, and antimicrobial resistance (AMR) in bacteria has worsened the scenario, requiring extensive research to find alternative therapeutic agents. Terpenoids play an essential role in protecting plants from herbivores and pathogens. The present study was designed to focus on in silico evaluation of terpenoids for their affinity towards two necessary enzymes, i.e. DHFR and DHPS, which are involved in forming 5, 6, 7, 8-tetrahydrofolate, a key component in bacterial DNA synthesis proteins. Additionally, to account for activity against resistant bacteria, their affinity towards the L28R mutant of DHFR was also assessed in the study. The structure-based drug design approach was used to screen the compound library of terpenes for their interaction with active sites of DHFR and DHPS. Further, compounds were screened based on their dock score, pharmacokinetic properties, and binding affinities. A total of five compounds for each target protein were screened, having dock scores better than their respective standard drug molecules. CNP0169378 (−8.4 kcal/mol) and CNP0309455 (−6.5 kcal/mol) have been identified as molecules with a higher affinity toward the targets of DHFR and DHPS, respectively. At the same time, one molecule CNP0298407 (−5.8 kcal/mol for DHPS, −7.6 kcal/mol for DHFR, −6.1 kcal/mol for the L28R variant), has affinity for both proteins (6XG5 and 6XG4). All the molecules have good pharmacokinetic properties. We further validated the docking study by binding free energy calculations using the MM/GBSA approach and molecular dynamics simulations.Communicated by Ramaswamy H. Sarma

Alzheimer's disease (AD) is a multifactorial neurological disorder that affects millions of people worldwide. Despite extensive research efforts, there are currently no effective disease-modifying therapeutics available for the complete cure of AD. In the current study, we have designed and synthesized a series of phenyl–styryl–pyrimidine derivatives as potential multifunctional agents against different targets of AD. The compounds were evaluated for their ability to inhibit acetylcholinesterase (AChE), monoamine oxidase (MAO) and β amyloid aggregation which are associated with the initiation and progression of the disease. Several compounds in the series exhibited potent inhibitory activity against AChE and MAO-B, with IC50values in the low micromolar range. In particular, two compounds, BV-12and BV-14, were found to exhibit a multipotent profile and showed non-competitive inhibition against MAO-B with IC50values of 4.93 ± 0.38 & 7.265 ± 0.82 μM, respectively and AChE inhibition with IC50values of 7.265 and 9.291 μM, respectively. BV-12and BV-14also displayed β amyloid self-aggregation inhibition of 32.98% and 23.25%, respectively. Furthermore, molecular modelling studies revealed that BV-14displayed a docking score of −11.20 kcal mol−1with MAO-B & −6.767 kcal mol−1with AChE, forming a stable complex with both proteins. It was concluded that phenyl–styryl–pyrimidine derivatives have the potential to be developed as multitarget directed ligands for the treatment of AD.

AbstractCancer is one of the most concerning diseases to humankind. Various treatment strategies are being employed for its treatment, out of which use of natural products is an essential one. Flavonoids have proven to be promising anticancer targets since decades. Also, tubulin is a significant biological target for the development of anticancer agents due to its crucial role in mitosis and abundance throughout the body. In the current study, in silicoADMET parameters of 104 flavonoids were examined, followed by molecular docking with the colchicine binding site of Tubulin protein (PDB; Id 4O2B). The best conformation from each flavonoid subcategory with the best docking score (MolDock score) was further subjected to 100 ns of molecular dynamics to investigate the protein-ligand complex’s stability. Different parameters such as RMSD, RMSF, rGy and SASA were calculated for the six flavonoids using molecular dynamic studies. The top most compound from all the six subcategories of flavonoids elicited best behavior in the colchicine binding site of Tubulin protein. This in silicostudy employing molecular docking and molecular dynamics simulation provides strong evidence for flavonoids to be excellent anti-tubulin agents for the treatment of cancer.Communicated by Ramaswamy H. Sarma

The increasing burden of microbial infection and emerging resistance against the available antimicrobial drugs drives the development of new agents. Two different series of indole-based compounds (VN-1 to VN-18) were synthesized and analyzed for antimicrobial activity by calculating the diameter of the inhibition zone using the broth dilution method and well diffusion method against Escherichia coli (E. coli) and environmental microbes. Most of the compounds displayed good to moderate activity against E. coli, and VN-4 and VN-9 displayed good inhibitory activity against the tested microbes. Molecular docking and binding energy calculation studies of all the synthesized compounds have been performed for targeting FabI, where most of the compounds showed significant interactions with the aromatic nicotinamide moiety of NAD+. In molecular dynamics studies, VN-9 stays inside the binding cavity for sufficient time to induce antimicrobial activity. Thus, these indole-based derivatives may lead to the development of new antimicrobial agents that may act as FabI inhibitors.