Letters in Drug Design & Discovery - Volume 17, Issue 9, 2020

Background: Over the last decade, there has been a sudden rise in the demand for herbal as well as Information and Technology (IT) industry around the world. Identification of plant species has become useful and relevant to all the members of the society including farmers, traders, hikers, etc. Conventional authentication techniques such as morphological characterization, histological methods, and optical microscopy require multiple skills which are tedious, timeconsuming and difficult to learn for non-experts. This creates a hurdle for individuals interested in acquiring knowledge of species. Relying on rapid, economical and computerized approaches to identify and authenticate medicinal plants has become a recent development. Objective: The purpose of this review is to summarize artificial intelligence-based technologies for wider dissemination of common plant-based knowledge such as identification and authentication to common people earlier limited to only experts. Methods: A robust plant identification design enabling automated plant-organ and feature-based identification utilizing pattern recognition and image processing techniques resulting in image retrieval and recognition has been highlighted in this review for all the concerned stakeholders. Attempts have been made to compare conventional authentication methods with advanced computerized techniques to emphasize the advantages and future applications of an automated identification system in countering adulteration and providing fair trade opportunities to farmers. Results: Major findings suggested that microscopical features such as shape and size of calcium oxalate crystals, trichomes, scleriods, stone cells, fibers, etc. are the essential descriptors for identification and authentication of herbal raw drugs using computational approaches. Conclusion: This computational design can be successfully employed to address quality issues of medicinal plants. Therefore, computational techniques proved as a milestone in the growth of agriculture and medicinal plant industries.

Background: Oleanolic Acid (OA) is a ubiquitous product of triterpenoid compounds. Due to its inexpensive availability, unique bioactivities, pharmacological effects and non-toxic properties, OA has attracted tremendous interest in the field of drug design and synthesis. Furthermore, many OA derivatives have been developed for ameliorating the poor water solubility and bioavailability. Objective: Over the past few decades, various modifications of the OA framework structure have led to the observation of enhancement in bioactivity. Herein, we focused on the synthesis and medicinal performance of OA derivatives modified on A-ring. Moreover, we clarified the relationship between structures and activities of OA derivatives with different functional groups in A-ring. The future application of OA in the field of drug design and development also was discussed and inferred. Conclusion: This review concluded the novel achievements that could add paramount information to the further study of OA-based drugs.

Background and Introduction: Sesquiterpene lactones are a class of secondary metabolite that contains sesquiterpenoids and lactone ring as pharmacophore moiety. A large group of bioactive secondary metabolites such as phytopharmaceuticals belong to this category. From the Asteraceae family-based medicinal plants, more than 5,000 sesquiterpene lactones have been reported so far. Sesquiterpene lactone-based pharmacophore moieties hold promise for broad-spectrum biological activities against cancer, inflammation, parasitic, bacterial, fungal, viral infection and other functional disorders. Moreover, these moiety based phytocompounds have been highlighted with a new dimension in the natural drug discovery program worldwide after the 2015 Medicine Nobel Prize achieved by the Artemisinin researchers. Objective: These bitter substances often contain an α, β-unsaturated-γ-lactone as a major structural backbone, which in recent studies has been explored to be associated with anti-tumor, cytotoxic, and anti-inflammatory action. Recently, the use of sesquiterpene lactones as phytomedicine has been increased. This study will review the prospect of sesquiterpene lactones against inflammation and cancer. Methods: Hence, we emphasized on the different features of this moiety by incorporating its structural diversity on biological activities to explore structure-activity relationships (SAR) against inflammation and cancer. Results: How the dual mode of action such as anti-inflammatory and anti-cancer has been exhibitedby these phytopharmaceuticals will be forecasted in this study. Furthermore, the correlation of anti-inflammatory and anti-cancer activity executed by the sesquiterpene lactones for fruitful phytotherapy will also be revealed in the present review in the milieu of pharmacophore activity relation and pharmacodynamics study as well. Conclusion: So, these metabolites are paramount in phytopharmacological aspects. The present discussion on the future prospect of this moiety based on the reported literature could be a guide for anti-inflammatory and anti-cancer drug discovery programs for the upcoming researchers.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutics; they are competitive inhibitors of cyclooxygenase (COX), the enzyme which mediates the conversion of arachidonic acid to inflammatory prostaglandins. Objective: In this study, new benzodioxol derivatives with different core cycles and functional groups (i.e., aryl acetate, aryl acetic acid and diazepine) were designed, synthesized, identified and evaluated for their analgesic and anti-inflammatory activity, as a preliminary screening study to identify the most potent and more selective groups. Methods: The synthesized compounds were identified using FTIR, HRMS, 1H-NMR and 13C-NMR, and evaluated for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay kit. Results and Discussion: Six compounds were synthesized as a preliminary screening study to identify which was the most potent and more selective group towards COX-2 versus COX-1, compared to ketoprofen as non-selective NSAIDs. The compounds have three different groups: aryl acetate, aryl acetic acid and diazepine. The results showed that the most potent compound against the COX- 1 enzyme was 4b (which has diazepine and 2-chlorophenyl) with IC50 = 0.363 μM, and the selectivity ratio of 4b was found to be better than ketoprofen. In contrast, compound 4a (which has diazepine and 3-chlorophenyl) was the most selective with a COX-1/COX-2 ratio value of 0.85 in comparison with a ketoprofen ratio value of 0.20. Conclusion: In general, the synthesized library has moderate activity against both enzymes (i.e., COX-1 and COX-2). Moreover, all six compounds have better COX-2 inhibition selectivity compared to the commercial drug ketoprofen.

Background: Drug delivery to the brain tumor is limited due to the presence of the blood-brain barrier (BBB). Objective: This study aimed to evaluate the therapeutic effects of cisplatin-loaded PEGylated liposomes, targeted with the OX26 antibody (targeted liposomal cisplatin) against transferrin receptor expressing rat glioma C6 cells in vitro. Methods: The liposomes were synthesized using reverse phase evaporation method and were conjugated to the OX26 monoclonal antibody. They were characterized in terms of size, drug encapsulation efficiency, morphology and drug release experiments using dynamic light scattering, atomic absorption spectrometry, scanning electron microscopy, and dialysis membrane methods. Then, their biological activities were evaluated on targeting the BBB. Results and Discussion: The characterization results showed that spherical nanodrug with a size of 157 nm and drug loading efficiency of 24% was synthesized, which released 64% of the loaded cisplatin after 72 h in a controlled release manner. The nanoparticles caused an increase in the cisplatin cytotoxicity effects by 1.7-, 1.8- and 1.8-fold, compared to cisplatin-loaded PEGylated liposomes (liposomal cisplatin) after 24, 48 and 72h incubation, respectively against C6 cells. Moreover, targeted liposomal cisplatin showed promising results in the transport of cisplatin across the BBB, in which it caused an increase in the cisplatin cytotoxicity on C6 cells by 2.7- and 2.4-fold, compared to cisplatin and liposomal cisplatin, respectively. Conclusion: Regarding the properties of the targeted liposomal cisplatin, it suggests that the potency of the formulation, to be evaluated, for the transport of cisplatin across the BBB, delivers it to the brain tumor in vivo.

Background: Bone remodeling is a complex process that includes continuous resorption by osteoclast cells and bone formation by osteoblast cells. Bone fragility is a common health issue of the elderly population, particularly in postmenopausal women. It has been established that steroidal hormones have an important role in bone homeostasis. Therefore hormone replacement therapy could have beneficial effects on bone health as compared to other treatments. Objectives: An imbalance between the rate of bone formation and bone resorption leads to the fragility of bones. During the current study, we aimed to explore the ability of pregnenolone (1) (PRE), on proliferation and differentiation of MC3T3-E1 cells. We further aimed to investigate the underlying mechanism of action for the anabolic effect of PRE (1). Methods: The effects of pregnenolone (1) on proliferation, differentiation, and mineralization of MC3T3 osteoblast-like cells were determined. Cell viability was analyzed using MTT assay and flow cytometry. ALP activity and alizarin staining were employed to evaluate the effect of pregnenolone on osteoblast differentiation. Moreover, western blot for analysis of certain important proteins, crucial for the regulation of bone homeostasis, such as BMP2 and RANKL, was also performed. Results and Discussions: Our results showed that pregnenolone (1) at a concentration of 5 μM caused a significant (p< 0.05) rise in the growth of MC3T3-E1 cells, whereas a comparable effect was observed in osteoblast differentiating assays. A significant decrease in RANKL expression was observed at (0.04 – 1 μM). Our results, therefore, indicated the possible role of pregnenolone (1) in positive regulation of bone homeostasis by suppressing RANKL expression. Conclusion: Taken together, our results indicate that pregnenolone (1) has the potential to enhance osteoblast proliferation, as inferred from the increased number of cells. These results demonstrated that pregnenolone (1) could be a potential anabolic agent for the treatment of fragility related disorders.

Background: Drug resistance by the cancer cells towards current chemotherapeutic approaches poses a great challenge. In the present study, an indole analogue of a well-known plant derived anticancer molecule, curcumin, was tested for its Multidrug Resistance (MDR) reversing potential in induced multi drug resistant A549 cell line. Materials and Methods: Human lung cancer cell line A549 was made Multidrug Resistant (MDR) by prolonged treatment with low dosage of Docetaxel, an established anticancer drug. The MDR induction was confirmed by morphological evidence, Hoechst 33342 staining, MTT assay, Rhodamine123 staining and RT-PCR of ABCB1 gene. Protein expression studies were carried out using western blotting technique. Results and Discussions: The induced MDR A549 cells exhibited significant increase in the gene expression of ABCB1 gene at the transcriptional level. Retention and efflux studies with Pglycoprotein (P-gp) substrate Rh123 indicated that indole curcumin inhibited P-gp mediated efflux of Rhodamine. Furthermore, treatment of MDR A549 cells with indole curcumin showed downregulation of gene expression of ABCB1 and COX 2. This was also confirmed from the decreased protein expression of COX 2. Conclusion: The results of the present study indicate that indole curcumin reverses multi drug resistance by downregulating the expression of ABCB1 and COX 2 genes. Thus, indole curcumin may act as a potent modulator for ABCB1 and COX 2 mediated MDR in lung cancer.

Background: Due to the complex etiology of AD, multi-target-directed ligands (MTDLs), combining two or more distinct pharmacological moieties, have been developed in both symptomatic and disease-modifying efficiencies and are considered as an effective way for the treatment of AD. Methods: To test their biological activities, including AChE/BChE inhibitory activity and MAOA/ MAO-B inhibitory activity. In addition, molecular modeling studies were performed to afford insight into the binding mode. Results and Discussions: The results displayed that compound 4c showed the best AChE inhibitory activity with an IC50 value of 4.2 μM, which was supported by the kinetic study and docking study. Compound 4c was also a selective MAO-B inhibitor (IC50 = 8.2 μM). Moreover, compound 4c could cross the blood-brain barrier in vitro. Conclusion: Compound 4c deserved to further study as a potential multifunctional agent for the treatment of Alzheimer’s disease.

Background: Hepatocellular Carcinoma (HCC) is a prevalent cancer in the world. As yet, there is no medication for complete treatment of HCC. Objective: There is a critical need to search for an innovative therapy for HCC. Recently, multiepitope vaccines have been introduced as effective immunotherapy approach against HCC. Methods: In this research, several immunoinformatics methods were applied to create an original multi-epitope vaccine against HCC consisting of CD8+ cytolytic T lymphocytes (CTLs) epitopes selected from α- fetoprotein (AFP), glypican-3 (GPC3), aspartyl-β-hydroxylase (ASPH); CD4+ helper T lymphocytes (HTLs) epitopes from tetanus toxin fragment C (TTFC), and finally, two tandem repeats of HSP70407-426 were used which stimulated strong innate and adaptive immune responses. All the mentioned parts were connected together by relevant linkers. Results and Discussions: According to physicochemical, structural, and immunological results, the designed vaccine is stable, non-allergen, antigen; it also has a high-quality 3D structure, and numerous linear and conformational B cell epitopes, whereby this vaccine may stimulate efficient humoral immunity. Conclusion: Center on the collected results, the designed vaccine potentially can induce cellular and humoral immune responses in HCC cases; nonetheless, the efficiency of vaccine must be approved within in vitro and in vivo immunological analyzes.

Background: Free radicals are the main cause of numerous diseases. Their overproduction needs to be controlled in order to combat several ailments. The current study deals with the discovery of new free radical scavengers. Methods: Substituted N-hydrazinecarbothioamide indazoles 1-18 were evaluated for DPPH and ABTS radical scavenging activities. Results and Discussions: All synthetic compounds possess good radical DPPH and ABTS scavenging potential in the ranges of IC50 = 2.11 ± 0.17 - 5.3 ± 0.11 μM and IC50 = 2.31 ± 0.06 - 5.5 ± 0.07 μM, respectively, as compared to standard ascorbic acid having IC50 = 2.02 ± 0.11 μM for DPPH and IC50 = 2.1 ± 0.07 μM for ABTS. Conclusion: These compounds could serve as leads for antioxidant activity that have the ability to control free radical generation and ward off free radical-induced disorders.

Background and Introduction: The availability of antiviral medicines for the treatment of viral diseases is limited, hence the discovery of novel bioactive molecules is required. The present investigation has been carried out to develop novel 3-O-sulfotransferase enzyme inhibitors to treat viral diseases. Methods: Virtual screening study (QSAR, docking and pharmacophore analysis) and binding mode analysis have been performed on a dataset collected from the literature (synthetic and natural compounds). Results and Discussion: The docking studies showed that Glu184, His186, Lys215 and Lys368 residues established the most important hydrogen bonding with several hit compounds. The QSAR results explained that the presence of electronegative atoms/groups in the aromatic or heteroaromatic rings confer increased activity. Furthermore, the flexibility and the aromatic rings with less polar groups have better activity than the compounds connected to purine rings. Finally, the structurebased pharmacophore studies illustrated that the ligand has many polar interaction sites, and the projected acceptor and donor groups in the molecules make a significant contribution to the pharmacophore model building. Conclusion: These studies identified two compounds, Phomoidride B and Barceloneic acid A, as potential 3-OST inhibitors.