Letters in Drug Design & Discovery - Current Issue

Chagas disease is a neglected disease caused by the protozoan Trypanosoma cruzi that affects 7 million people worldwide. The current treatment is limited due to safety and efficacy issues. Therefore, the search for new antiparasitic drugs is fundamental. The enzyme squalene synthase (SQS) is an attractive therapeutic target since it participates in the ergosterol biosynthesis pathway.

In the present study, we explored the Brazilian biodiversity to search for potential inhibitors of T. cruzi SQS (TcSQS) using ligand and structure-based virtual screening strategies.

A virtual screening was performed within the NuBBE database, with more than 2,200 natural products (NP) or semisynthetic derivatives from the Brazilian biodiversity. Molecular docking and ADMET predictions were then performed.

A set of 12 NP showed interactions with TcSQS like those observed by known inhibitors and shared literature evidence that supports the predicted activity.

Three compounds (flavonoids) showed good ADMET properties as potential inhibitors of TcSQS.

Methylene blue and some of its analogues have known antibacterial activity, however their exact mechanism of action is unknown.

In this study, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of several methylene blue analogues were determined against five bacterial strains, whereafter the data were used to create and validate a pharmacophore model.

The agar dilution method was used to screen the analogues for antibacterial activity, while the broth microdilution method was used to determine their MIC and MBC. A pharmacophore model was constructed and validated using the rank score, fit value, enrichment factor (EF^10%), hit rate (HR^10%) and receiver operating characteristic area under the curve (ROC-AUC) as metrics.

Against Staphylococcus aureus, pyronin B (0.125 µg/ml) was more active than tetracycline 
(1 µg/ml) and pyronin Y (0.5 µg/ml), 1,9-dimethylmethylene blue (2 µg/ml), basic blue 3 (2 µg/ml), new methylene blue (2 µg/ml) and Nile blue (2 µg/ml) had similar activity compared to tetracycline. Pyronin B, 1,9-dimethylmethylene blue and new methylene blue were bactericidal. A pharmacophore model was created (rank score: 36.55, max. fit value: 3), which was able to identify active analogues out of the test set (EF^10%: 2.83, HR^10%: 28.57%, ROC-AUC: 0.84 ± 0.04). The pharmacophore model highlighted that a positive ionisable, aromatic ring as well as a hydrophobic moiety are important for antibacterial activity.

Methylene blue analogues were found to have potent antibacterial activity and a pharmacophore model was created to understand the structural requirements for activity.

Cinnamic acid, derived from Cinnamomum cassia, is a natural compound known for its wide-ranging therapeutic properties and minimal toxicity. Extensive research has demonstrated the diverse biological activities displayed by cinnamic acid derivatives, encompassing their potential as agents against cancer, diabetes, microbial infections, tuberculosis, malaria, and more.

This review aims to provide an overview of the latest applications detailing the biological activity of cinnamic acid derivatives, as documented in patents.

The published patent data underwent a prior screening and selection process based on their relevance and primary focus: the biological activities of cinnamic acid derivatives as potential drugs. Espacenet, USPTO, and Google Patents were used for this selection.

Cinnamic acid derivatives demonstrate a range of activities, including anticancer, antibacterial, anti-inflammatory, analgesic, anticholinesterase, and other properties. These biological activities were investigated across different derivatives, emphasizing their pharmacological potential when compared to reference compounds.

Despite several patents have explored the biological properties of cinnamic acid derivatives, there has been a lack of a comprehensive review dedicated to this subject. Accordingly, this review aims to facilitate the discovery of new and diverse potential drugs with various therapeutic profiles.

Colorectal cancer is the third foremost cause of death in women and men. Globally, about 1.94 million colon cancer cases were diagnosed and around 0.93 million patients died in the previous year.

Several drugs have been permitted by the Food And Drug Administration (FDA) for the treatment of colorectal cancer. The main difficulties of current drugs are the expansion of resistance issues, target selectivity issues and toxicity issues. The existing therapies, such as surgery and hormonal therapy, are in use but exhibit numerous adverse effects, such as pharmacokinetic issues and pharmacodynamic issues. Hence, hereby is a crucial requirement of novel moieties that are peaceable and efficient in the handling of colorectal cancer.

Phthalazine derivatives have expanded admiration over a few years due to their efficient anticancer significance. These Phthalazine derivatives exhibit anticancer activity by targeting various mechanisms such as apoptosis induction, tubulin polymerization inhibition, EGFR inhibition, and aurora kinase inhibition.

In this study, we have focused on the Structural Activity relationship, numerous synthetic strategies and mechanism of action of phthalazine derivatives for potential treatment of cancer.

Among some of phthalazine derivative compounds not only induced antiproliferative activity even also improve bioavailability and reduce side effects, like 4-(phthalazine-1-yl) aniline with (IC50 = 0.22 ± 0.11 μM), and 4-phthalazin-1-yl-amino) benzonitrile (IC50 = 1.20 μM), 4-((5-methyl-pyrazole-3-yl) amino)-2-phenylphthalazin-1-one (IC50 = 0.031 μM) and 4-((5-methyl-pyrazole-3-yl) amino)-2-(p-tolyl)phthalazin-1-one (IC50 = 0.065 μM). Therefore, this study would be the inspiration for the betterment of human health.

Inflammation is the first response and an alarming signal for the onset of chronic disease. Most of the anti-inflammatory drugs available in the market are reported to have undesirable gastrointestinal toxicities. Therefore, it is of urgent significance to develop anti-inflammatory drugs with low toxicity and good efficacy.

We created a targeted scaffold based on a literature review by combining the different structural characteristics of furan and benzyl amides into a single pharmacophore. A series of eighteen furan-based derivatives (1-18) were designed, synthesized for in vitro and in vivo anti-inflammatory activity. The characterization of synthesized compounds was elucidated by techniques like ¹H-NMR, ¹³C-NMR, FT-IR and MS.

The synthetic compounds were examined through molecular docking studies on TNF-α for probable binding mode and interactions with hydrophilic and hydrophobic pocket of TNF-α in comparison to standard drug (Indomethacin).

When compared to the standard treatment, compounds 18, 15 and 9 displayed a remarkable inhibitory effect on the production of TNF-α and in vivo inflammatory activity with no damage to stomach and reduction of LPO. The compounds 18, 15 and 9 might be a good consideration for potential anti-inflammatory agents.

As cancer stands as a significant global health concern, many heterocyclic compounds that are more effective in cancer cells than healthy cells are being investigated for their selective anticancer potentials. One such compound is fenretinide, a synthetic derivative of retinoic acid that has a broad spectrum of cytotoxic activity against primary tumor cells, cell lines, and/or xenografts of various cancers. In this context, bexarotene and its derivatives, synthesized from hybridization of the fenretinide, are expected to possess a potential anticancer activity.

The objective of the present study was to investigate the synthesis of novel amid-derived and bexarotene-based compounds, as well as to assess their cytotoxic effects in different cancer cell lines.

This study involved the synthesis of twelve novel retinoid derivatives (6-17) in a six-step process. The cytotoxic activities of these compounds were assessed against various cancer cell lines, such as A549 (human lung carcinoma), HeLa (human cervical cancer), MCF7 (human breast adenocarcinoma), and WiDr (human colon adenocarcinoma). The chemical structures of these compounds were elucidated through their elemental analysis, mass spectrometry (ESI⁺, ESI^-), as well as ¹H-NMR and ¹³C-NMR spectroscopic data.

The obtained cell toxicity results indicated that compounds 6, 8, 11, 12, 13, 14, and 17 were found to exhibit the strongest cytotoxic activity in above mentioned cancer cell lines. The IC50 values for active compounds, 11 and 12, were determined as 2.38µM and 2.29µM, respectively. Remarkably, these compounds displayed higher cytotoxic activity in the WiDr cell line related to positive control, camptothecin (CPT). Moreover, compounds 14 and 17 demonstrated very similar level of cytotoxic activity to CPT, indicating their potential for antitumoral applications upon further studies.

While compounds 11, 12, 14, and 17 indicated a very comparable anticancer activity to CPT, compounds 6, 8, 11 and 12 showed more selective anticancer effect against cancer cells than non-cancerous cells. In accordance with the findings of the present study, they can be evaluated as primary candidates for further studies, specifically as RXRα-targeted anticancer agents.

Baricitinib (BCTB) is a novel Janus Kinase (JAK) 1 and 2 inhibitor used in the therapy of rheumatoid arthritis, approved by the “Food and Drug Administration” in 2018. It has significant dose-dependent effectiveness and severe side effects. Thus, it is crucial to figure out its concentration in developed dosage forms. The literature search revealed that there has only been one UV spectroscopy technique documented up to this point. Methanol was chosen as the detection medium in this approach, which is not comparable with plasma or serum. As a result, the preliminary research suggested developing a UV spectroscopic approach that can estimate BCTB concentration and compare it to its concentration in the plasma or serum. Thus, in the proposed method, 7.4 pH phosphate buffer was selected as a mobile phase.

Using the Analytical Quality by Design (AQbD) methodology, a simple, robust spectrophotometric method for the detection of BCTB in API form and Niosomes drug delivery system is designed and assessed.

In the AQbD approach, a face-centered CCD design of Design Expert 13 software was used to evaluate two critical method variables: scanning speed and sampling interval. The design space suitability was confirmed by standard error and overlay plots. The 2-D contour and 3-D response surface plots were used to forecast the relationship between the response variable and predictor variables.

Baricitinib displays an absorption maximum at 249.40 nm in saline phosphate buffer pH 7.4. The distinguished linearity of the method was obtained over a concentration of 5-30 µg/ml with a correlation coefficient (R²) value of 0.998. BCTB % assay was found to be near 99%. Intraday and Interday precision were found to have % RSDs of 0.067-0.488 and 0.146-0.942, respectively.

The established spectrophotometric technique was observed to be precise as per ICH revised guidelines ICH Q2 (R1) and Q14 for analytical method validation. Our findings are instructional for the future design and development of safe and reliable therapeutic dosage forms of BCTB for rheumatoid arthritis.

People with type 1 diabetes mellitus (T1DM) are significantly more likely to have osteoporosis (OP). Astragali Radix is a Chinese herbal medicine containing various active ingredients, and several clinical trials have been reported to use it to treat OP and T1DM, respectively.

To evaluate the targets and potential mechanisms of Astragali Radix administration on OP and T1DM.

The targets of Astragali Radix were identified using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The OP and T1DM datasets were downloaded from the Gene Expression Omnibus (GEO) database. The weighted gene correlation network analysis (WGCNA) method was used to identify the co-expression genes associated with OP and T1DM. In addition, the common gene targets of OP and T1DM were screened using two public databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R tool. After the validation of key genes, molecular docking was performed to visualize small molecule-protein interactions.

The compound target network mainly contained 17 compounds and 147 corresponding targets. There were 561 GO items and 154 signaling pathways in KEGG, mainly including the AGE-RAGE signaling pathway in diabetic complications and osteoclast differentiation. The results of molecular docking showed that flavonoids were the top compound of Astragali Radix, which had a high affinity with CDK2, VEGFA, and MYC.

Flavonoids in Astragali Radix may regulate multiple signaling pathways through MYC, CDK2, and VEGFA, which may play a therapeutic role in OP and T1DM.

This study aimed to investigate the protective effects of phytosomal curcumin and/or shilajit in reducing post-surgical tendon adhesion band formation in a rat model.

Tendon adhesion is one of the severe complications after tendon surgery which causes limited tendon movement and functional disability.

According to the central role of inflammatory reactions in fibrosis and the formation of tendon adhesions, we investigated the therapeutic effects of phytosomal curcumin and shilajit either alone or in combination on reducing post-surgical tendon adhesion band formation in a rat model.

We randomly divided 36 Wistar male rats into six equal groups. (A) Control group with no surgical incision and no intervention. (B) Sham group with surgical incision, but no adhesion, (C) Positive control group with total surgical transection and adhesion receiving normal saline daily, (D-F) Treatment groups which are the same as group C except that rats were treated with the following drugs. Phytosomal curcumin alone (250 µL/day; orally), shilajit alone (500 mg/kg/day; orally) and a combination of phytosomal curcumin + shilajit. In groups with surgical intervention, the rats' Achilles tendons were cut and repaired with a modified Kessler technique. At 3 weeks, all rats were euthanized. Histological and pathological scoring systems were used to evaluate the protective effects of phytosomal curcumin and/or shilajit in reducing adhesion bands at the site of tendon injuries.

Our results revealed that the administration of phytosomal curcumin and/or shilajit remarkably reduced length, density, grading, severity, and thickness of post-surgical adhesion bands. Compared to the untreated control group, the histological changes and inflammatory reactions were significantly attenuated in treated rats. Furthermore, treatment with phytosomal curcumin and/or shilajit inhibited fibrotic responses by alleviating collagen deposition, fibrosis quantity, fibrosis grading, and total fibrosis scores, as visualized by Masson’s trichrome staining.

Our findings indicated the anti-inflammatory and anti-fibrotic properties of phytosomal curcumin and/or shilajit supporting their therapeutic potential in preventing post-operative tendon adhesion bands.

Chronic myeloid leukemia (CML) is considered a type of hematopoietic stem cell disease that affects the bone marrow and blood.

This study aimed to investigate the possible role of the Periplaneta americana extract CII-3 (PAE CII-3) in the aging of K562 cells.

The proliferation and cell cycle of K562 cells were determined using the CCK-8 assay and the cell cycle assay, respectively. K562 cells were stained with SA-β-Gal to evaluate cell aging. The mitochondrial membrane potential of K562 cells was detected with the JC-1 mitochondrial membrane potential assay kit. Telomerase activity was verified using the PCR assay. The transcription of silencing information regulator 2 related enzyme 1 (SIRT1), TSC2, and the mTOR gene were evaluated with RT-PCR assay. The expression of SIRT1, p-TSC2, and p-mTOR was examined using a Western blot assay.

PAE CII-3 at all concentrations (5, 10, 20, 40, 80, 160 μg/mL) demonstrated obvious inhibitory effects on K562 cell proliferation, among which 80 μg/mL showed the highest inhibitory effect. PAE CII-3 significantly blocked the cell cycle and reduced the colony-forming unit (CFU) of K562 cells compared to those in the Control group (p < 0.001). PAE CII-3 markedly increased positive SA-β-Gal staining K562 cells compared to the Control group (p < 0.001). PAE CII-3 significantly reduced mitochondrial membrane potential and decreased TERT gene transcription in K562 cells compared to those of the Control group (p < 0.001). The transcription of the SIRT1 gene (p < 0.01) and the TCS2 gene (p < 0.001) was markedly decreased, and the transcription of the mTOR gene (p < 0.05) was significantly increased in K562 cells treated with PAE CII-3 compared to those of the Control group. PAE CII-3 significantly decreased the expression of SIRT1 (p < 0.01) and p-TSC2 (p < 0.001) and upregulated the expression of p-mTOR (p < 0.01) in K562 cells compared to those of the Control group.

PAE CII-3 treatment could trigger aging in K562 cells by activating the SIRT1/TSC2/mTOR signaling pathway. This study would provide a potential hypothesis of the mechanism by which PAE CII-3 treatment induces the aging of chronic myeloid leukemia cells.

Globally, hepatitis B and C infect 400 million people, more than 10 times the number of people living with HIV. In 2019, it was estimated that 1.1 million people died as a result of the disease (PAHO/WHO, January 2023).

This study aimed to conduct a computational analysis of the proteins that express the hepatitis virus envelope glycoproteins in order to gain insight into their function.

Different computational tools were used to calculate the Polarity Index Method 2.0 v (PIM 2.0 v) profile (previously titled Polarity Index Method profile) and the Protein Intrinsic Disorder Predisposition (PIDP) analyzed for each sequence, in addition to computational tools that made it possible to revise these proteins at the genetic level.

Both the PIM 2.0 v profile and the PIDP profile of various hepatitis B and C virus envelope glycoproteins were able to reproduce the structural and morphological similarities that they had previously. The presence of certain patterns in each of these profiles made this accomplishment feasible.

Computational programs could reproduce characteristic PIM 2.0 v profiles of the hepatitis B and C virus envelope glycoproteins. This information is useful for a better understanding of this emerging virus.

Mentha piperita, a naturally occurring herb, is utilized in medicinal formulations. It possesses abundant bioactive elements, including flavonoids and phenolic acid compounds, that exhibit various properties such as antioxidants, anti-inflammatory and anti-cancer.

In the present study, chemical constituents of essential oil extracted from Mentha piperita were analyzed and identified through GC-MS. In vitro antiproliferative activity was performed on A549 lung cancer cell line lines. In silico study was conducted by Schrodinger’s Maestro’s software to identify chemical constituents in the plant as potential EGFR (Epidermal Growth Factor Receptors) inhibitors.

Hydro-distilled essential oil was analyzed by GC-MS to identify chemical components based on the retention index and mass fragmentation pattern, which was then tested for its antiproliferative activity by MTT assay against human lung cancer cell lines. All the identified constituents were investigated in silico for their affinity towards EGFR (Epidermal Growth Factor Receptors).

A total of thirty constituents were identified where D-carvone (56.69%), L-limonene (12.36%), squalene (3.36%), cis-carveol (2.93%), and α-amorphene (2.36%) were observed as major constituents of the essential oil. The essential mentha oil also exhibited antiproliferative activity against lung cancer cell lines with an IC50 value of 86.05 µg/ml. Furthermore, from the in silico study, five constituents were identified to have a better affinity for EGFR (Epidermal Growth Factor Receptors) than that of the standard drug Osimertinib.

In the present study, the aerial part of the plant Mentha piperita was hydrodistilled. Thirty phytoconstituents were identified through GC-MS data. An in-silico study was performed using Schrodinger software, and a further in vitro study was performed in which essential oil showed good anti proliferative activity against the A549 cancer cell line.

Parkinson’s disease (PD) is a prevalent neurological disease characterized by the gradual degeneration of dopaminergic neurons leading to a dysfunctional central nervous system. Recently, major metabolites of Coffea arabica leaves were revealed to exhibit good electron-shuttling potential in Microbial Fuel Cells (MFCs), similar to neurotransmitters dopamine and epinephrine.

This In silico study aimed to identify the neuroprotective potentials of plant metabolites from coffee leaves and to determine their physicochemical and pharmacokinetic properties for developing viable anti-parkinsonian drug design.

Molecular docking was performed to evaluate the affinity of identified major compounds in C. arabica against PD-target proteins and compare the results with the binding activity of existing drugs and natural ligands of the identified protein targets via LibDock scores. The drug-likeness and ADMET profiles of each ligand were also evaluated using bioinformatics tools.

C. arabica metabolites exhibited various degrees of binding activity against PD targets. LibDock scores of test compounds showed that catechin, mangiferin, and chlorogenic acid exhibited higher docking scores than dopamine and levodopa. Physicochemical and pharmacokinetics analysis of the selected molecules revealed caffeine, catechin, and chlorogenic acid as promising candidates for drug development with a low risk of drug toxicity.

The present study indicates that Coffea arabica leaves contain promising neuroprotective active compounds against Parkinson’s disease.

Parkinson’s Disease is one of the leading neurodegenerative disorders in the world. Currently, there is still no treatment that could completely cure the disease. Traditional Chinese Medicine has been a source for drug candidates, and many studies have elucidated its pharmacokinetic capabilities. Previous studies showed that Magnolia officinalis has anti-inflammatory, antioxidant, and bioenergy generation activities. Furthermore, the electron-shuttling and bioenergy-stimulating capabilities of herbal and brain disorder medicines have been linked to their effectiveness as a remedy.

This preliminary study aims to evaluate the electron-shuttling compounds of Magnolia officinalis (i.e., acteoside, isoquercitrin, magnatriol B, obovatol, quercitrin, randaiol, and rutin) as potential drug candidates for Parkinson’s Disease.

The seven electron-shuttling compounds were individually docked to the five Parkinson’s Disease-related proteins, namely aromatic L-amino acid decarboxylase, α-synuclein, monoamine oxidase B, catechol-o-methyltransferase, and A2A adenosine receptor, using LibDock. ADMET predictions were also made to screen the compounds further.

Molecular docking results showed that all compounds have relatively high LibDock scores against the proteins, with acteoside, isoquercitrin, and rutin having the highest scores. However, considering the ADMET results, only magnatriol B, obovatol, and randaiol had optimal properties as candidates for neurodegenerative drugs.

The electron-shuttling compounds of M. officinalis, magnatriol B, obovatol, and randaiol, have the potential to be a remedy for Parkinson’s Disease due to their high probability of binding to the proteins.

Epidermal growth factor tyrosine kinase receptor (EGFR) is expressed in a variety of tumors and has become a new target for anti-cancer drugs. In recent years, small molecule inhibitors targeting EGFR have been reported extensively.

To investigate the quantitative structure-activity relationship (QSAR) of a set of EGFR inhibitors and design several new EGFR inhibitors with better efficiency and selectivity.

The structure–activity relationship of 119 pyrimidine EGFR inhibitors were studied based on comparative field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMISA).

In this study, performance models with high prediction ability were constructed (CoMFA model: q²= 0.574, r²= 0.970, SEE= 0.163, F= 407.252; CoMSIA model: q²= 0.575, r²= 0.968, SEE= 0.171, F= 286.102), according to which 9 new EGFR inhibitors were designed. MD simulation (100 ns) on the docked complex of compound N7 (the most active compound) shows that the small molecule bindswith the protein stably.

The newly designed compound N7 was considered to be a promising EGFR inhibitor with better activity than the best active compound 80, according to the results of molecular docking, molecular dynamics, and ADMET prediction. These results will provide valuable guidance for the design of novel EGFR inhibitors.

Vinpocetine (Vinp), a derivative of alkaloid vincristine with anti-inflammatory and antioxidant effects, has been shown to have neuroprotective effects in Parkinson's disease (PD). Its role and mechanisms, however, are not fully understood. Therefore, the aim of this study was to investigate the effects and possible mechanisms of Vinp on PD cells.

SH-SY5Y cells were treated with Vinp and then with rotenone to induce a cellular model of PD. The proliferation level and apoptosis rate of SH-SY5Y cells after different treatments were detected by MTT and flow cytometry assays, respectively. Western blot was used to determine the relative protein expression of α-Synuclein (α-Syn) in differently treated cells. Additionally, commercial kits and ELISA were used to determine oxidative stress-related indicators (superoxide dismutase (SOD), malondialdehyde (MDA), and reactive oxygen species (ROS)) and inflammatory factors (tumor necrosis factor α [TNF-α], interleukin-5 (IL-5), and interleukin-1β (IL-1β)) in SH-SY5Y cells after different treatments, respectively.

Vinp at different concentrations (5, 10, and 50 μM) had no significant effect on the proliferation and apoptosis of SH-SY5Y cells. For rotenone-induced SH-SY5Y cells, Vinp pretreatment could significantly reduce α-Syn expression, increased cell viability and decreased apoptosis, oxidative stress (downregulation of ROS and MDA levels and upregulation of SOD activity) and inflammation (increased levels of TNF-α, IL-5, and IL-1β). In contrast, overexpression of α-Syn in SH-SY5Y cells with Vinp pretreatment and rotenone induction partially reversed the aforementioned protective effects of Vinp, causing a decrease in proliferation, an increase in apoptosis rate, inflammation, and oxidative stress.

Vinp exerted neuroprotective effects by downregulating α-Syn to promote proliferation, inhibit apoptosis, and inhibit oxidative stress and inflammation in rotenone-induced SH-SY5Y cells.