Current Computer - Aided Drug Design - Volume 17, Issue 5, 2021

Background: The aminopeptidase N (APN) over-expressed in tumor cells plays a critical role in angiogenesis which makes the development of APN inhibitors an attractive strategy for cancer research. Aims and Objectives: It is clinically significant to develop potential APN inhibitors for cancer treatment. The design, synthesis, biological evaluation and molecular simulation of mandelic acid peptidomimetic derivatives as APN inhibitors are reported. Materials and Methods: Analysis of the binding mode of bestatin to APN led to the design and synthesis of mandelic acid peptidomimetic derivatives. APN inhibitory activities in vitro were evaluated by the spectrophotometric method. The binding mode of the target compounds with the APN binding site was studied relying on docking studies, molecular dynamics simulation experiments and binding energies calculation. Results: The structures of target compounds were confirmed by IR, ¹H-NMR and MS. All compounds exhibited a different range of inhibitory ability with IC50 values lying in the micromolar level. The compound 9m was found to be most potent as compared to other target derivatives. The molecular simulation revealed that ligand coordinating with the catalytic zinc ion is very important for inhibitory activities. Conclusion: The compound 9m might represent a promising scaffold for the further development of novel anti-cancer drugs.

Background: Aurora kinases (AKs) belong to the serine/threonine kinase family and play a crucial role in regulating the cell cycle. Therefore, AKs are the hopeful target for anticancer therapies and these findings have encouraged researchers to rigorously hunt small molecule aurora kinase inhibitors, not only for research articles but also for use as therapeutic agents. Objective: The present study helps us to identify and screen the best phytochemicals as potent inhibitors against AKs. These potent inhibitors come from the various substitution of rosmarinic acid (RA). Methods: In this paper, we choose different tested derivative compounds for designing anticancer drugs by substituting various functional groups of standard drug RA. In silico studies were carried out to appreciate better drug candidature of some of these derivative compounds. This study was performed on 56 derived compounds of the standard RA. DFT study was conducted using the UB3LYP/6-311++G(d,p) basis set to study HOMO-LUMO energies, dipole moments, using the Gaussian16 suite. Some of the derived parameters, like ionization potential, electron affinity, softness- hardness, chemical potential, and electrophilicity index were noted. A docking study was performed with AKs inhibiting receptor using AutoDock 4.2. ADME prediction was made with the preADMET web tool. Molecular descriptor properties were predicted with molinspiration and OSIRIS property explorer. Results: Out of the 56 derivatives, 11 have passed all the rules of drug candidature, to serve as best AKs inhibitor, in a theoretical manner. Conclusion: This study should be supported by a new proposal to explore future studies with these 11 compounds against cancer.

Background: β-amyloid (Aβ) production and aggregation are the main culprits of Alzheimer’s disease (AD). There is no treatment available for halting the disease progression. Antibiotics are used not only to treat infections but also to some of the non-contagious diseases and have found active as anti-amyloidogenic agents. Objective: The aim of this work is to investigate anti-amyloidogenic activity of antibiotics as repurposing agents via inhibiting Aβ aggregation and fibril formation employing in silico and in vitro approaches. Methods: In silico screening was designed with receptor and ligand preparation, grid formation, docking simulation and its analysis. Thioflavin T-amyloid binding and protease-digestion studies were intended as in vitro assays. These methods assessed the pharmacological potential of antibiotics as anti-amyloidogenic agents. Results: Paromomycin and Neomycin were identified with a higher order of estimated free energy of binding in in silico experiments. In in vitro screening, paromomycin significantly (p<0.01) reduced the fluorescence intensity and resistance to tryptic degradation of Aβ(1-42) peptides while neomycin had no or little effect (p<0.01) when compared to control. Results from docking and wet lab studies were found in correlation. Conclusion: Paromomycin exhibited higher anti-Aβ aggregating and defibrillogenic activity than neomycin and left an indication for further in vivo testing and could be a future promising antiamyloidal candidate for the treatment of several amyloidoses.

Aim and Objective: Isoflavone phytoestrogens, commonly present in natural plants, are closely related to human health. The combination of them with estrogen receptors in the body can play an important role in the prevention and treatment of cardiovascular diseases, cancer, and menopausal diseases. This research is conducted for the wider application of isoflavone phytoestrogens in various fields. Methods: In this study, molecular docking studies and molecular dynamics simulations were performed to explore the affinities and interaction between three typical isoflavone phytoestrogens and estrogen receptors (ERα and ERβ), respectively. Results: Molecular docking results showed that the affinity of genistein, daidzein, and formononetin was different, and the ligand structures and hydrogen bonds force were the main factors affecting the binding abilities. Conclusion: The calculation of the binding free energy shows the stability of the complex and the contribution of various interactions to the binding free energy. The decomposition of binding free energy indicates that van der Waals interaction and electrostatic interaction promote the binding of the complex, which are in agreement with the docking studies.

Background: The STE20/SPS1-related proline/alanine-rich kinase (SPAK) is a component of WNK-SPAK/OSR1 signaling pathway that plays an essential role in blood pressure regulation. The function of SPAK is mediated by its highly conserved C-terminal domain (CTD) that interacts with RFXV/I motifs of upstream activators, WNK kinases, and downstream substrate, cation- chloride cotransporters. Objective: To determine and validate the three-dimensional structure of the CTD of SPAK and to study and analyze its interaction with the RFXV/I motifs. Methods: A homology model of SPAK CTD was generated and validated through multiple approaches. The model was based on utilizing the OSR1 protein kinase as a template. This model was subjected to a 100 ns molecular dynamic (MD) simulation to evaluate its dynamic stability. The final equilibrated model was used to dock the RFQV-peptide derived from WNK4 into the primary pocket that was determined based on the homology sequence between human SPAK and OSR1 CTDs. The mechanism of interaction, conformational rearrangement and dynamic stability of the binding of RFQV-peptide to SPAK CTD were characterized by molecular docking and molecular dynamic simulation. Results: The MD simulation suggested that the binding of RFQV induces a large conformational change due to the distribution of salt bridge within the loop regions. These results may help in understanding the relationship between the structure and function of SPAK CTD and to support the drug design of potential SPAK kinase inhibitors as antihypertensive agents. Conclusion: This study provides deep insight into the SPAK CTD structure and function relationship.

Background: The chalcones were reported to have many biological activities by showing affinity towards many enzymatic targets. The effect of nitric oxide (NO) on calcium channel was extensively studied in different animals; the study was also carried out for NO donor drug and its effect on calcium channel. Till date, the inhibition of calcium channel is of prime importance in the medicinal chemistry to discover newer vascular smooth muscle relaxant drugs. Objective: The main objective of this work is to carry out in silico and in vitro evaluation of NO donor chalcones for calcium channel blocking potency. Methods: The present work includes in silico evaluation of chalcone derivatives for calcium channel blocking potency. The promising scaffolds were identified after pharmacophore modeling and docking study. The in vitro screening of 21 lead molecules for calcium channel blocking potency was carried out on pulmonary veins of adult goat, IC50 values were determined and 3D QSAR was performed. Results: The pharmacophore modeling revealed that hydrogen bond donor, hydrogen bond acceptor, and hydrophobic groups are important features for calcium channel blocking activity. The docking study revealed the existence of hydrophobic, hydrogen bond and Vander wall's interactions between amino acid residues and ligands. The in vitro screening showed that the compounds AI6, Ca2, and D8 were potent, produced 4.756, 3.608 and 5.211 μM of IC50 respectively, whereas the standard Nifedipine showed the potency of 1.304 μM of IC50. The 3D QSAR study explained the importance of different steric and electrostatic parameters and their correlation for L type calcium channel blocking activity. Conclusion: This study showed that the chalcone scaffold with NO donor capacity is promising for designing novel calcium channel blockers to treat vascular disorders.

Aim: The aim of the study was to find out the role of auranofin as a promising broadspectrum antibacterial agent. Methods: In vitro assays (Percentage growth retardation, Bacterial growth kinetics, Biofilm formation assay) and In silico study (Molegro virtual docker (MVD) version 6.0 and Molecular operating environment (MOE) version 2008.10 software). Results: The in vitro assays have shown that auranofin has good antibacterial activity against Gram positive and Gram negative bacterial strains. Further, auranofin has shown synergistic activity in combination with ampicillin against S. aureus and B. subtilis whereas in combination with neomycin has just shown additive effect against E. coli, P. aeruginosa and B. pumilus. In vivo results have revealed that auranofin alone and in combination with standard drugs significantly decreased the bioburden in the zebrafish infection model as compared to control. The molecular docking study have shown good interaction of auranofin with penicillin-binding protein (2Y2M), topoisomerase (3TTZ), UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosaminedeacetylase (3UHM), cell adhesion protein (4QRK), β-lactamase (5CTN) and arylsulphatase (1HDH) enzyme as that of reference ligand which indicate the multimodal mechanism of action of auranofin. Finally, MTT assay has shown the non-cytotoxic effect of auranofin. Conclusion: In conclusion, auranofin in combination with existing antibiotics, could be developed as a broad spectrum antibacterial agent; however, further studies are required to confirm its safety and efficacy. This study provides the possibility of the use of auranofin apart from its established therapeutic indication in combination with existing antibiotics to tackle the problem of resistance.