Letters in Drug Design & Discovery - Volume 20, Issue 1, 2023

Cancer is a condition in which body cells grow uncontrollably and spread to other parts of the body or grow at a particular location. Depending on their location, cancer is named or categorized. Breast cancer is the second most constantly determined and one of the prime reasons for cancer death among females. Many external factors like carcinogenic agents and internal factors like genetic factors are responsible for causing breast cancer in females. Additionally, the threat of breast cancer occurrences increases with age and non-success in treatment. The current methods and treatments utilized in treating, diagnosing and predicating breast cancer in the present world are not very advanced. Therefore, over time, the desire to analyze the factors facilitating the succession of breast cancer, prediction, and reduction in the time taken for diagnostics, treatment, and drug discovery for breast cancer has increased. However, traditional methods make it hard to study prediction, diagnostics, treatment, and drug discovery for breasts. Therefore, computational approaches like artificial intelligence, bioinformatics, quantitative structure-activity relationship (QSAR) studies, and molecular docking are used to analyze those things. This article discusses current trends in computational chemistry in different fields

The dosing pattern of the conventional drug delivery system results in continuously changing and unpredictable plasma concentrations as this system has modest control on the release of the drug along with almost negligible effectual concentration near the site of interest. The problems coupled with conventional drug delivery can be triumphed over by employing osmotic drug delivery systems, which are one of the most budding strategies utilizing osmotic pressure to release active pharmaceutical ingredients in an optimized manner at a controlled rate. Various formulation parameters which influence the release of drugs from these systems include osmotic pressure wielded by the core components, the drug’s solubility, and the size of the delivery orifice in conjunction with the characteristics of the semipermeable membrane. However, it is completely autonomous of the gastrointestinal tract’s anatomical environment and concomitant meal ingestion. The aim of this manuscript is to study the earlier osmotic pumps, their working principles, along with their limitations, and novel approaches having significant benefits over older ones. The current manuscript covers all the aspects of the osmotic drug delivery system, including its principle of osmosis, the historical background, its advantages and disadvantages, basic components, various factors influencing its design, its various types, and evaluation parameters. Novel approaches to osmotic drug delivery systems along with future prospective have also been described.

Aims: The synthesis of bioactive compounds has antioxidant potential. Background: All aerobic bodies including human beings, have antioxidant defense systems that protect them from oxidative damage, and many enzymes to remove or heal damaged molecules. However, this normal antioxidant mechanism can be incompetent, and hence dietary intakes of antioxidant compounds are important. Objective: This study aimed to synthesize isophthalate Schiff base derivatives 1-14 and screen them for their antioxidant activities (DPPH, ferrous ion Fe²⁺ chelating, and ferric Fe³⁺ reducing activities). Methods: Schiff bases 1-14 were synthesized by a two-step reaction scheme. The first step was the esterification reaction of isophthalic acid followed by the hydrazinolysis of methyl isophthalate to afford isophthalic dihydrazide. The second step was the condensation reaction of isophthalic dihydrazide with various benzaldehydes to afford Schiff bases 1-14. Synthetic compounds were characterized by spectroscopic techniques such as ¹ H-NMR and EI-MS. Results: Compounds were screened for their antioxidant activities (DPPH, ferrous ion Fe²⁺ chelating, and ferric Fe³⁺ reducing activities). Most of the compounds showed significant antioxidant activities. A structure- activity relationship has also been discussed. Conclusion: Most of the synthetic isophthalate Schiff bases were found to be moderately active when screened for their antioxidant activities by three assays such as DPPH radical scavenging, ferrous ionchelating, and ferric reducing activities. These moderately active compounds can serve as lead molecules to further modify the structure and identify more powerful antioxidant agents.

Background: Heterocyclic compounds are vital for research due to their diverse pharmacological profiles. They are key structural components of many of the potent antimicrobial drugs available on the market today but still facing the problem of drug resistance by microbes. Indole and its derivatives display versatile pharmacological activities, such as analgesic, antimicrobial, antidepressant, antidiabetic, anti-convulsant, antihelmintic, and anti-inflammatory. Objective: Indole ring was linked to other key heterocyclic moieties, such as morpholine, imidazole, piperidine, and piperazine at the active 3rd position by Schotten-Baumann reaction, and further evaluated against Gram-positive and Gram-negative bacteria with the hope to develop potent antimicrobial agents. Methods: Synthesis of derivatives was performed under appropriate conditions and characterized by IR, NMR (¹H and ¹³C), and CHN elemental analysis. Further, in vitro assays were used to evaluate their antimicrobial activity by agar diffusion and agar streak dilution method against Bacillus subtilis (ATCC 6633) and Escherichia coli (ATCC 25922). ADME properties were also calculated using the Swiss ADME online program. Results: Compounds 4b, 4f, 4i, 4k showed maximum potency in both in vitro assays calculated as the zone of inhibition (17±0.5 mm-22±0.25 mm) and minimum inhibitory concentration (MIC= 6.25-25 μg/ml)) comparable to standard drugs ciprofloxacin and ampicillin. ADME results showed zero violation of the Lipinski’s rule. Conclusion: A great deal of work has been done on the synthesis and evaluation of indole derivatives to explore their antimicrobial effect. These findings may lead to the design and development of more effective antimicrobial drug candidates.

Introduction: The Diphtheria vaccine is currently manufactured by chemical inactivation of Diphtheria toxin (DT) following large-scale cultivation of the pathogenic Corynebacterium diphtheriae. The development of non-toxic variants of DT in non-pathogenic recombinant hosts improves the process safety aspects considerably and is therefore desirable. The cytotoxicity of DT was exerted through ADPribosylation of elongation factor 2 (EF2) by the catalytic (C) domain of DT using NAD as the ADP donor. Aim: We, therefore, aim to design DT variants unable to perform ADP-ribosylation of EF2. Methods: We used molecular dynamics simulations (MDS) for docking of the C-domain of DT onto EF2 to identify interacting amino acid fluctuations using the root mean square fluctuation (RMSF). Amino acids of the C domain possessing low fluctuations and hence low flexibility were then specified and used for the mutant design. The C domain and the mutants were docked with NAD and ADENYLYL-3'-5'- PHOSPHO-URIDINE3'-MONOPHOSPHATE (APU) as a C domain inhibitor. G52E showing negligible NAD binding was also included in our study. Free binding energies of the complexes were calculated and used to select the desired mutants. Moreover, contact maps of the C domain and the selected mutants were compared to elucidate their structural differences. The SCRATCH tool was used to estimate their solubility upon recombinant expression in E. coli. ElliPro was further used to determine their B-cell epitopes. Results: Our results indicated that amino acids Y20, V80, V81, V83, and Y149 within the C domain showed low flexibility. The constructed mutants, including Y20E and Y80E were able to bind APU, whereas Y149E was not able to bind it. Both Y20E and Y149E were unable to bind NAD. Thus, these mutants did not have ADP-ribosylation activity and were nontoxic. These were structurally different from the C domain. However, their solubility in E. coli and their conformational B-cell epitopes were similar to those of the C domain. Conclusion: Therefore, Y20E and Y149E are applicable for the vaccine design with DT using a much safer process compared to the commercial process.

Background: Alzheimer's disease (AD) is the most common brain disorder and remains a major health concern worldwide. Considering the highly complex mechanisms of AD, the search for agents based on a multitarget-directed ligands (MTDLs) strategy to treat AD may be more promising than the traditional “one drug-one target” strategy. Inhibition of Poly (ADP-ribose) polymerases-1 (PARP-1) has a potentially therapeutical effect on AD. Therefore, it is worthy to investigate compounds that target both PARP-1 and cholinesterase, which perhaps produces new agents against AD. Objective: To search for new agents with PARP-1 and cholinesterase inhibitory activities for the treatment of AD. Methods: A series of 21 novel compounds incorporated the respective pharmacophores of two marketed drugs, namely the 4-benzyl phthalazinone moiety of a PARP-1 inhibitor, Olaparib, and the Nbenzylpiperidine moiety of an AChE inhibitor, Donepezil, into one molecule was synthesized. The inhibitory activities of all the synthesized compounds against the enzymes PARP-1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were evaluated. The binding modes of the most potent compound inside the PARP-1 and the human BChE (hBChE) were investigated by molecular docking. Results: N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1, 2-dihydro-1-oxophthalazin-4- yl)methyl)benzamide (30) exhibited the most potent inhibitory effect on PARP-1 enzyme (IC50=8.18±2.81nM) and moderate BChE inhibitory activity (IC50=1.63±0.52μM), while its AChE inhibitory activity (IC50=13.48±2.15μM) was weaker than Donepezil (IC50=0.04±0.01μM). Further molecular docking studies revealed that four hydrogen bonds were formed between 30 and PARP-1, meanwhile, 30 interacted with the critical residues His438 and Trp82 of hBChE through hydrogen bonds and hydrophobic interactions, which were necessary for hBChE inhibitory potency. Conclusion: A new compound with potent PARP-1 inhibitory activity and moderate BChE inhibitory activity was obtained, which merited to be further investigated as an anti-AD drug. The studies gave a clue to search for new agents based on PARP-1 and cholinesterase dual-inhibited activities to treat AD.

Objective: The study aims to explore the mechanism of Qingchang Suppository in the treatment of ulcerative colitis from the perspective of network pharmacology. Methods: The TCM Pharmacology database and analysis platform (TCMSP) were used to determine the effective components and related target information of the Qingchang Suppository. The main objective is to search the target genes related to ulcerative colitis using the GeneCards database. The target abbreviation is transformed into gene number by Perl language. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was analyzed by R language. The pharmacological mechanism of Qingchang supply was discussed, laying the foundation for the next experiment. Results: 869 indexes of Qingchang Suppository were determined. 368 targets of ulcerative colitis were obtained. Qingchang Suppository and ulcerative colitis were compared, and 141 overlapping targets were extracted. The "active ingredient target" network of Qingchang Suppository was constructed. The interaction between the effective components of Qingchang Suppository and the target of ulcerative colitis was revealed. The overlapping targets were analyzed for the KEGG pathway and function enrichment to explore the mechanism of Qingchang Suppository in the treatment of ulcerative colitis. Conclusion: Qingchang Suppository has the characteristics of multi-component, multi-target and multichannel, which provide a new idea and basis for further study on the mechanism of Qingchang Suppository in the treatment of ulcerative colitis.

Background: Studies have shown that epigallocatechin-3-gallate (EGCG), which is present in green tea at a higher rate than other components, has an additive or synergistic cytotoxic effect when applied with different anticancer drugs and reduces the side effects caused by anticancer drugs. It is known that the order of administration of drugs in combined applications also affects cytotoxicity. In this context, our study determined the most effective application sequence by evaluating the cytotoxic responses of epirubicin-HCl and EGCG according to the different application orders in A-549 cells (NSCLC). Methods: To demonstrate the apoptotic activity, we detected changes in mRNA ratios of Bax, a proapoptotic gene, and Bcl-2, an anti-apoptotic gene (Bax/Bcl2), as well as changes in the activity of caspase 3/7 enzyme. To demonstrate the effect of oxidative stress generation, we investigated changes in glutathione peroxidase activity. Results: It was observed that the cell viability of A-549 cells exposed to different concentrations of epirubicin- HCl and EGCG for 48 h decreased depending on the concentration increase. According to the results of cell viability in cells to which epirubicin-HCl (< IC50) and EGCG (< IC50) were treated together, and the combination index (CI) value calculations, the most effective combination concentrations were determined to be IC20 Epirubicin-HCl and IC10 EGCG. LDH activities were higher in epirubicin-HCl + EGCG treatment than in the epirubicin-HCl alone treatment compared to control groups. Treatment of epirubicin-HCl with EGCG was found to be more effective in increasing glutathione peroxidase activity than epirubicin-HCl alone. Both epirubicin-HCl alone and combination treatments caused an increase in Bax/Bcl-2 ratio in A-549 cells. Conclusion: Combination therapy of epirubicin-HCl with EGCG may be helpful in the future for lung cancer patients trying to be treated with conventional chemotherapy drugs but cannot achieve the desired success.

Background: Nepeta binaludensis Jamzad is a perennial medicinal plant with various pharmacological effects. However, the neuroprotective effects of Nepeta binaludensis extracts have not yet been investigated. This study aimed to examine the effects of N. binaludensis hydro-alcoholic extract (NBE) on oxidative stress markers and apoptosis-related proteins in PC12 cells exposed to oxygen-glucose deprivation/ reperfusion (OGD/R). Methods: PC12 cells were pretreated with NBE (at a concentration range of 10-200 μg/ml) before exposure to the OGD condition for 6 h, followed by a 24 h reoxygenation. Cell viability, the production of the reactive oxygen species (ROS), lipid peroxidation (LPO), and the levels of apoptosis-related proteins were evaluated using MTT, fluorimetry, and western blot analysis, respectively. Results: Survival of the cells preincubated for 6 h with NBE increased to 90.20 ± 15.62% compared with those subjected to OGD/R alone (51.26 ± 7.77 %, p < 0.001). ROS formation was also decreased following incubation with 200 μg/ml of NBE to 125.3 ± 18.38% compared to OGD/R group (356.9 ± 70.48%, p < 0.001). LPO was also suppressed after incubation with NBE to 155.5 ± 21.21% compared to the OGD/R group (260.5 ± 9.727%, p<0.001). NBE restored Bax/Bcl-2 ratio (1.3-fold of control), and cleaved caspase-3 (1.58-fold of control, p < 0.001). Conclusion: These results suggest that NBE may offer neuroprotection properties against OGD/Rinduced toxicity through modulation of oxidative stress and apoptotic responses.

Background: HSP90, a critical molecular chaperone, has become a promising molecular target to be involved in multiple signaling pathways of tumor progression and metastasis. Objective: This study intends to find a novel phytolead targeting HSP90. Methods: In this scenario, we employed an in silico combinatorial approach incorporating 3D-QSAR, pharmacophore generation, pharmacokinetics, docking, MD simulation and metabolism studies. Results: To find a natural novel compound targeting HSP90, a ligand-based pharmacophore model was developed, exploiting 17 diversely classified training set molecules with known experimental activity exhausting the pharmacophore generation (HypoGen algorithm) module of Discovery Studio. The bestdeveloped hypothesis (Hypo1) was employed against the UNPD database to screen lead compounds targeting HSP90. Pterodontoside G (Asteraceae family)became a potent compound with the fit value of 8.80 and an estimated activity of 3.28 nM. Pterodontoside G was taken forward for analog design and pharmacokinetics studies, followed by docking and MD simulation studies. UNPD1 came out to be the best analog following all pharmacokinetics properties with the highest binding energy in comparison with the parent compound and the standard drug (Ganetespib). It mapped all the features of Hypo1 with a fit value of 8.68 and an estimated activity of 4.314 nM, exhibiting greater binding stability inside the active site of HSP90 causing no conformational changes in the protein-ligand complex during MD analysis. Conclusion: The result was further supported by PASS analysis and xenosite reactivity data proposing UNPD1 to hold potent antiangiogenic potential targeting HSP90.

Background: Benzoylureas are the most commonly used chitin synthesis inhibitors. But, the exact target site of benzoylurea insecticides has not been identified. Objective: To study whether benzoylphenylureas analogues with a bipartite model could be designed and synthesized as novel insecticides with improved activities. Methods: Based on the bipartite model of the sulfonylurea receptor binding site and commercial diflubenzuron, a series of novel benzoylureas containing carbamate groups were designed and synthesized via the key intermediate 2,6-difluoro-N-((4-hydroxyphenyl)carbamoyl)benzamide (2). The structures of the target compounds were confirmed by the ¹H NMR and high-resolution mass spectrum (HRMS). Results: The results of bioassays indicated that these target compounds possessed good larvicidal activities against a broad spectrum of insects such as oriental armyworm (Mythimna Separata Walker), diamondback moth (Plutella xylostella), and mosquito (Culex pipiens pallens). A compound containing N, N-diisopropyl (3g) exhibited the highest insecticidal activity against oriental armyworm (40% at 10 mg kg^-1), which was comparable with that of diflubenzuron. These compounds also had good larvicidal activities against diamondback moth and mosquito; most of these target compounds exhibited comparable larvicidal activities of diamondback moth with diflubenzuron and higher larvicidal activities of mosquito than diflubenzuron. Conclusion: The experimental data above preliminarily proved the rationality of our speculation and design ideology, and BPUs analogues with a bipartite model could improve the interaction with the target.