Letters in Drug Design & Discovery - Volume 19, Issue 1, 2022

Drug resistance confronts chemotherapy of neoplasm and microbial infections. A vast array of molecular mechanisms was implicated in drug resistance, including generation of drug efflux transporters, mutation of drug targets, and alteration of drug metabolism. With the alarming rate of increase in drug resistance, pathogens are bolstering in such a way that many new drugs face efficacy problems within a short span of entry into the market. Evolution is the driving force towards the development of drug resistance. By adopting the modern genomic and functionomic analytical techniques, scientists have now identified novel genes and signalling proteins involved in the evolution of drug resistance in microorganisms. Given the current knowledge of bacterial evolution, antibiotic drug discovery is ready for a paradigm shift to explore the newer ways to tackle drug resistance. The article discusses such recent developments and reviews their merits and demerits in an attempt to envisage the findings in this new domain of medicine.

Background: Infectious diseases, as well as cancer, are the leading causes of death worldwide. Drug resistance usually results in their treatment requiring a combination of two or more drugs. Objective: Oleanolic-based hybrid compounds were prepared via esterification and characterized using FTIR, NMR and LC-MS. In vitro antibacterial and in vitro cytotoxicity studies were performed. Methods: Oleanolic acid was hybridized with selected known pharmaceutical scaffolds via the carboxylic acid functionality in order to develop therapeutics with increased biological activity. Antibacterial activity was determined using the micro-dilution assay against selected Gram-positive and Gram-negative bacteria and cytotoxicity using the sulforhodamine B assay. Results: Compound 8 displayed potent antibacterial effect against five strains of bacteria, such as Bacillus subtilis, Staphylococcus aureus, Proteus vulgaris, Klebsiella oxytoca, and Escherichia coli, with MIC values of 1.25, 0.078, 0.078, 1.25, 1.25 mg/mL when compared to the control, oleanolic acid (MIC = 2.5 mg/mL). Furthermore, in vitro cytotoxicity, as determined using the SRB assay, against selected cancer cells revealed that compound 7 was the most cytotoxic on MDA, DU145, and MCF-7 cell lines with IC50 values of 69.87 ± 1.04, 73.2 ± 1.08, and 85.27 ± 1.02 μg/mL, respectively, compared to oleanolic acid with an IC50 > 200 μg/mL. Conclusion: Hybridization of oleanolic acid was successful, and further development of these potential antibacterial compounds with reduced cytotoxicity is therefore warranted.

Background: Platelet-activating factor (PAF) is an agonist mediator in the inflammatory process, which interacts with PAF receptor (PAFR) that eventually causes cancers, respiratory and neurodegenerative diseases. This interaction activates the mitogen-activated protein kinase (MAPK) pathway, leading to a pro-inflammatory cascade. The pathophysiological conditions due to activation of inflammatory cascade could be inhibited by PAF antagonists. Objectives: In this study, selected naturally derived flavonoids (flavone, biochanin A, and myricetin) with different functional groups were subjected to molecular modelling and experimental studies to investigate their potential as PAF antagonists. Methods: Interactions of flavonoids and PAF were assessed via Autodock Vina for molecular docking and the AMBER program for molecular dynamic simulations. The experimentally antagonistic effects of the flavonoids were also conducted via PAF inhibitory assay to determine the IC50 values. Results: The findings of docking and dynamic simulations have revealed that all selected flavonoids interact with PAFR in the binding site with considerably good binding affinity up to - 9.8 kcal mol^-1 as compared to cedrol (- 8.1 kcal mol^-1) as a standard natural PAFR antagonist. The PAFR-flavonoid complexes exhibited four conserved active site residues, which included W73, F97, F174, and L279. The stability of all complexes was attained in a 30 ns simulation. The findings of in silico analyses were then compared to the experimental study on PAF inhibitory assay. Inhibitory effects of flavonoids against PAFR showed moderate activities, ranging from 27.8 – 30.8 μgM^-1. Conclusion: All studied flavonoids could act as promising PAF antagonists with some enhancement in their structures to exhibit potent antagonistic activity. However, these naturally derived flavonoids demand further investigation at cellular and animal models to develop new PAF antagonist drug candidates for treating PAF-mediated diseases.

Aims: Repurposing of drugs has been hypothesized as a means of identifying novel treatment methods for certain diseases. Background: Glioblastoma (GB) is an aggressive type of human cancer; the most effective treatment for glioblastoma is chemotherapy, whereas, when repurposing drugs, a lot of time and money can be saved. Objective: Repurposing of the existing drug may be used to discover candidate drugs for individualized treatments of GB. Methods: We used the bioinformatics method to obtain the candidate drugs. In addition, the drugs were verified by MTT assay, Transwell® assays, TUNEL staining, and in vivo tumor formation experiments, as well as statistical analysis. Results: We obtained 4 candidate drugs suitable for the treatment of glioma, camptothecin, doxorubicin, daunorubicin and mitoxantrone, by the expression spectrum data IPAS algorithm analysis and drug-pathway connectivity analysis. These validation experiments showed that camptothecin was more effective in treating the GB, such as MTT assay, Transwell® assays, TUNEL staining, and in vivo tumor formation. Conclusion: With regard to personalized treatment, this present study may be used to guide the research of new drugs via verification experiments and tumor formation. The present study also provides a guide to systematic, individualized drug discovery for complex diseases and may contribute to the future application of individualized treatments.

Background: Ulcerative colitis (UC); an inflammatory bowel disease primarily affects the mucosa of the colon. Depending on its mode of appearance, it can affect either the entire colon or even the distal rectum. UC can manifest in both genders and every generation, but most generally appear in people between the ages of 15 and 30. The extracellular matrix protein-1 (ECM1) gene is an important candidate, mutations leading to tissue damage in patients with ECM1 single-nucleotide polymorphisms are likely to intensify tissue damage caused by Metalloproteinase9 resulting in UC. Methods: In this analysis, approval for the synthesis of Chemical Compound was obtained from the scientific committee of the Department of Traditional Chinese Medicine, Qilu Hospital, China. Several derivatives used as UC therapy were selected to build the pharmacophore model, using a ligandbased pharmacophore modeling approach and virtual screenings were done for the identification of suitable drug compounds. The selected compound was then synthesized in-vitro and validated using the molecular docking technique. Results: The synthesized compound fulfills all the characteristics of the non-toxic existence of other drug-likeness laws. The specific interactive amino acids found in the docked complex are arginine (ARG):47, lysine (LYS):54, phenylalanine (PHE):141, aspargine (ASN):51, serine (SER):219, histadine (HIS):144, PHE:214, valine(VAL):220, tyrosine(TYR):145, and TYR:284. The interaction of the synthesized compound with mutated TYR:284 of ECM1 confirmed the viability and safety of a drug molecule as a medication in Ulcerative Colitis care. Conclusion: In the future, its validity can be explored in the laboratory and this synthesized compound can be used as a medication target in clinical studies against TYR:284 mutation in the ECM1 gene.

Background: In recent years, the number of people infected with the hepatitis C virus (HCV) is increasing rapidly. This has become a major threat to global health, therefore, new anti- HCV drugs are urgently needed. HCV NS5B polymerase is an RNA-dependent RNA polymerase (RdRp), which plays an important role in virus replication, and can effectively prevent the replication of HCV sub-genomic RNA in daughter cells. It is considered a very promising HCV therapeutic target for the design of anti-HCV drugs. Methods: In order to explore the relationship between the structure of benzimidazole derivative and its inhibitory activity on NS5B polymerase, holographic quantitative structure-activity relationship (HQSAR) and Topomer comparative molecular field analysis (CoMFA) were used to establish benzimidazole QSAR model of derivative inhibitors. Results: The results show that for the Topomer CoMFA model, the cross-validation coefficient q² value is 0.883, and the non-cross-validation coefficient r² value is 0.975. The model is reasonable, reliable, and has a good predictive ability. For the HQSAR model, the cross-validated q² value is 0.922, and the uncross-validated r² value is 0.971, indicating that the model data fit well and has a high predictive ability. Through the analysis of the contour map and color code diagram, 40 new benzimidazole inhibitor molecules were designed, and all of them have higher activity than template molecules, and the new molecules have significant interaction sites with protein 3SKE. Conclusion: The 3D-QSAR model established by Topomer CoMFA and HQSAR has good prediction results and the statistical verification is valid. The newly designed molecules and docking results provide theoretical guidance for the synthesis of new NS5B polymerase inhibitors and for the identification of key residues that the inhibitors bind to NS5B, which helps to better understand their inhibitory mechanism. These findings are helpful for the development of new anti-HCV drugs.

Background: Prostate cancer is the second most common cancer worldwide. The androgen deprivation therapy or castration leads to the recurrence of castration-resistant prostate cancer after some time. Androgen receptor is one of the most promising targets for the treatment of prostate cancer. The health benefits of phytoestrogens led us to explore them for their androgen receptor inhibition potential that may lead to inhibition of initiation and progression of prostate cancer. Methods: Protein-ligand interaction plays a central role in structure-based drug design, so we screened 23 phytoestrogens for their binding affinity to the androgen receptor using the molecular docking approach. These phytoestrogens were also tested for their ADME and toxicity profiles using the software. Results: Based on binding affinity, interacting amino acid residues, pharmacokinetics and toxicity profile, four phytoestrogens, namely naringenin, luteolin, hesperetin, and biochanin A were shortlisted as lead molecules. Conclusion: Therefore, our study has shown that these four phytoestrogens could be promising candidates for further evaluation for prostate cancer treatment or management.