Letters in Drug Design & Discovery - Volume 21, Issue 6, 2024

Background: Tirzepatide (LY3298176) was approved by U.S. Food and Drug Administration (FDA) on May 13th, 2022. The drug was developed by Eli Lilly and Co. and marketed under the trade name of ‘Mounjaro’, a first-in-class ‘Twincretin’, which is a dual activator of GIP and GLP-1 receptors, resulting in improved blood sugar control in type 2 diabetics The review covered the comprehensive insight on the drug discovery journey of tirzepatide. Methods: Using the keywords "Tirzepatide", "Twincretin", "Type 2 Diabetes", "GLP-1", and "GIP," data were gathered from Medline, PubMed, Google Scholar, and Science Direct. Results: The review covers comprehensive insight into the drug discovery journey of tirzepatide. The drug-target structural specialty has been discussed to establish the dual inhibition mechanism of action of tirzepatide. The results of in vitro studies, preclinical and clinical trial data, pharmacokinetic profile, dosing regimen, side effects, and toxicities of tirzepatide are reviewed to account for the potency, efficacy, and safety of the newly approved drug. The drug molecule may attain a privileged status in the antidiabetic market as the clinical data showed that it effectively reduces HbA1c level in monotherapy as well as in add-on therapy, compared to placebo, semaglutide, insulin degludec, and insulin glargine, and found effective in type 2 diabetes associated conditions like atherogenic dyslipidemia and non-alcoholic steatohepatitis. Conclusion: Tirzepatide is a clinically efficient drug, exhibiting a good safety profile as evident from the existing clinical data, and could be a new alternative to the currently available antidiabetics for the treatment of T2D.

Heterocyclic compounds are fundamental building blocks for developing novel bioactive compounds. Due to their extensive uses in both industrial and synthetic organic chemistry, quinoline and benzimidazole have recently become important heterocycles. Clinical trials have investigated quinoline and benzimidazole analogues to treat a variety of illnesses, including cancer, bacterial and fungal infection, DNA damage, etc. Medicinal chemists are paying attention to nitrogen-containing hybrid heterocyclic compounds that have a wide range of therapeutical potential with lesser adverse effects. Many efforts have been made to find new and more efficient ways to synthesize these molecules. However, microbial resistance is becoming a major threat to the scientific community; hence, the necessity for the discovery and development of novel antimicrobial drugs with novel modes of action is becoming highly significant. One strategy to overcome this problem is to produce hybrid molecules by combining two or more bioactive heterocyclic moieties in a single molecular platform. Based on established research data on quinoline- bearing benzimidazole derivatives, it can be concluded that both moieties are used for the synthesis of promising therapeutically active agents. This present review comprises the synthetic approaches of biologically active quinolines containing benzimidazole derivatives with their structure-activity relationship studies to provide an overview of the work done on quinoline derivatives to the medicinal chemist for future research.

Background: Despite being a normal body response against invading agents, inflammation, when exaggerated, needs to be controlled to minimize damage to the body. There are several drugs in clinical use against inflammation and other inflammatory conditions. Still, side effects often limit the use of these drugs, such as gastrointestinal effects generated by COX-1 inhibitors and cardiovascular effects by COX-2 inhibitors. Thus, exploring new targets such as mPGES-1 may lead to discovering agents that are more selective against inflammation and generate fewer side effects. Objectives: Here, docking, molecular dynamics, and MM-PBSA studies were performed on a dataset of known mPGES-1 inhibitors to identify helpful information and discover new mPGES-1 inhibitors. Methods: Molecular docking in GOLD software was used to obtain the complexes used in Molecular dynamics simulations (GROMACS software), performed to generate the RMSD, RMSF, Rg, SASA, and H-bond plots to predict the complexes' stability. The most stable conformation was analyzed regarding the most important interactions of the compounds. Finally, MM-PBSA calculations using the tool g_mmpbsa in GROMACS software were performed to determine de-binding affinity, interaction parameters, and per-residue contribution. Results: The main findings of this work were that the molecular dynamics simulation was able to find the open conformation of mPGES-1, which showed a greater preference on compounds in this region, consisting of residues known as "gateways". All compounds showed stability and stable complex formation with mPGES-1, as demonstrated by the results of RMSD, RMSF, Rg, SASA, and H-bond plots generated in a molecular dynamics simulation at 100 ns. The molecular dynamics identified three preferential sites of interaction for the compounds. Thus, the docking and dynamics protocols showed greater affinity of these compounds for cavity-02, interacting with Leu⁸⁵, Pro⁸¹, Gln¹³⁴, Cys¹³⁷, Ala¹³⁸, and Ala¹⁴¹. On the other hand, compound 09 preferred the cavity-03 of the protein, interacting mainly with His⁷² through Hbond. In addition, MM-PBSA calculations showed binding energies of up to -220,113 KJ/mol for compound 04. Furthermore, MM-PBSA could identify which electrostatic interactions are the most prevalent in the complex formation of the compounds with the highest affinity (04 and 07). Still, the van der Waals interactions are the most important for the others. Finally, the energy contribution per-residue revealed Lys¹²⁰, Arg¹²², Arg¹²⁶, and Tyr¹³⁰ as the most important for the formation of the complexes. Conclusion: Design mPGES-1 inhibitors based on the residues Leu⁸⁵, Pro⁸¹, Gln¹³⁴, Cys¹³⁷, Ala¹³⁸, and Ala¹⁴¹, in addition to Lys¹²⁰, Arg¹²², Arg¹²⁶, and Tyr¹³⁰ can provide new promising drugs useful against diseases involving inflammatory conditions.

Background: Pseudomonas aeruginosa is a common cause of nosocomial infection worldwide and is responsible for 18-61% of deaths alone. The organism has gained resistance to many known antibiotics and evolved into a multidrug-resistant strain. The LptD outer membrane protein of P. aeruginosa is a special target of interest due to its role in outer membrane biogenesis. Objective: The study aimed to gain an insight into how mutations affect the overall properties of antimicrobial peptides and to identify novel peptide analogs against P. aeruginosa. Methods: The peptide analogs were designed and shortlisted based on physicochemical parameters and estimated free energy change in the current study. The docking studies for wild type and shortlisted peptides were performed against LptD protein of P. aeruginosa. The toxicity, allergenicity, and solubility analyses of peptide analogs with high binding affinity to LptD were also conducted. Results: The molecular docking results indicated that peptide analogs 523M26, 523M29, 523M34, and 523M35 for AP00523 (wild type); 608M12, 608M13, 608M19, 608M31, 608M32, 608M39, and 608M43 for AP00608 (wild type); and 2858M25 for AP02858 (wild type) bound effectively with LptD membrane than their wild types. The toxicity, allergenicity, and solubility analyses revealed all these peptide analogs to be nontoxic, non-allergen, and have good water solubility. Conclusion: The binding energies predicted 523M26, 608M39, and 2858M25 bind effectively to LptD proteins than their wild type. Based on docking analysis, it was further predicted that 608M39 has an estimated binding affinity greater than L27-11, which is a known peptidomimetic inhibitor of the LptD protein.

Background: Worldwide, millions of people are affected by neurodegenerative diseases. Even though treatment may help to reduce some of the mental or physical symptoms connected with neurodegenerative diseases, there is at present no way to slow disease development and no recognized cure. Objective: The current study was carried out to explore the cholinesterase (ChE) inhibitory properties of the stem of Piper betle and correlate them with in silico docking results of its phytoconstituents. Methods: The dried Piper betle stem was used to be extracted with purified water by using the maceration technique. The resultant was assessed for ChE inhibitory activity using Ellman’s method. The inhibitory profile of the aqueous extract of Piper betle (AEPB) stem was compared with rivastigmine, which is a standard cholinesterase inhibitor. The phytoconstituents of AEPB were procured from various literature studies. In silico docking studies were carried out with the help of AutoDock 4.2 software. Results: AEPB considerably inhibited AChE and BuChE with the inhibition constant values of 0.437 ± 0.62 μg/ml and 0.371 ± 0.62 μg/ml, respectively, in a dose-dependent manner. In computational evaluation, the selected phytoconstituents exhibited excellent binding interactions prevailing with cholinesterase targets than the standard rivastigmine. Conclusion: Based on the in vitro and in silico evaluations, Piperol A showed notable concentrationdependent inhibition of AChE and BuChE. These in vitro analyses and molecular docking studies will be helpful for the development of potent ChE inhibitors for the management of Alzheimer’s disease.

Background: Overexpressed CDK1 and CDK2 are targeted as potential sites for cancer treatment. Annona muricata fruit has been reported to have more than 100 acetogenins showing cytotoxic activities against cancer cell lines. Hence the study aims to demonstrate the cytotoxicity of ethyl acetate fruit extract, its role in cell cycle progression, and apoptosis using the MDMBA-231 breast cancer cell line. Docking, dynamics, and ADME studies were also demonstrated to generate lead molecules of AM fruit responsible for cancer treatment. Methods: Cell viability was quantified by the MTT assay. Cell cycle arrest and apoptotic cells were determined by flow cytometry and PI annexin V-FITC staining by flow cytometry, respectively. Molecular docking, molecular dynamics, and ADME properties of 11 acetogenins were studied using the schrödinger maestro suite 2018-1. Results: The MTT assay revealed IC50 232.9μg/ml with a high degree of cytotoxicity. The extract effectively caused cell cycle arrest at the G2M and S phases; early and late apoptosis was induced at 160 μg/ml and 320 μg/ml. Docking scores of muricin L, J, and annomuricin A complexed with CDK2 and muricin J, K, and L with CDK1 binding energy ranging is mentioned as a molecular dynamic study envisaged muricin j against CDK2 stable hydrogen and hydrophobic interactions with critical residues like ASP-86, GLN-131, HIS-84, LYS-89, PHE80, PHE82, and PHE83 throughout 200 ns (hinge region). ADMET profiling also confirmed that all 11 ligands passed the rule of 5 and 3. The in vitro and in silico studies revealed that these acetogenins could be CDK1 and CDK2 inhibitors for cancer treatment. Conclusion: The in vitro studies presume that the ethyl acetate fruit extract of AM is an excellent cytotoxic agent. In silico studies demonstrated that muricin j could lead molecules to target kinase proteins responsible for cell proliferation. ADME study enlightened us to take 11 acetogenins for the drug discovery process in managing cancer treatment.

Objective: To explore the autophagic effect of baicalein on acute myeloid leukemia (AML) cell lines, HL-60 and THP-1, and miR-424, which regulates the baicalein effect on HL-60 and THP-1 in which autophagy was observed. Methods: The cell counting kit-8 (CCK-8) assay was used to detect the optimal concentration of baicalein in the HL-60 and THP-1 cell lines. miR-424 was detected by qPCR. The influence of baicalein on the autophagy of the HL-60 and THP-1 cells was demonstrated by detecting the expression of Beclin-1, LC3- I, and LC3-II using western blot. The phosphatase and tensin homolog (PTEN)/PI3K/AKt/mTOR pathways were determined by western blot. Results: The optimum concentration of baicalein used and the time of treatment in the HL-60 and THP-1 cell lines were 40 μM and 48 hours, respectively. The expression of miR-424 in the baicalein-treated cells was lower than that in the blank group both in the HL-60 cells and THP-1 cells. The expression of PTEN was promoted by baicalein. However, baicalein inhibited PI3K expression, mTOR phosphorylation, and AKT phosphorylation in the two cell lines. LC3-133;/133;¡, which is the biomarker for autophagy, increased after the cells were treated with baicalein. The baseline expression also increased after the cells were treated with baicalein. Conclusion: Baicalein could promote the autophagy of the HL-60 and THP-1 cells via miR-424 and the PTEN/ PI3K/AKT/mTOR pathway.

Background: Human estrogen receptor alpha (ERα), which is known to play a role in mediating cell proliferation, metastasis, and resistance to apoptosis, is one of the targets of breast cancer therapies. Alpha mangostin (AM) is an active xanthone compound from Garcinia mangostana L. which has activity as an ERα inhibitor. Objective: This research aims to predict the pharmacokinetic and toxicity, and to study the molecular interactions of AM derivatives with the ERα using computer-aided simulation approaches through molecular docking, molecular dynamic, and pharmacophore screening to develop novel anti-breast cancer agents. Methods: Marvinsketch and Chimera programs were used to design and optimize the structure of AM and its derivatives. For screening the pharmacokinetic and toxicity profiles, the PreADMET web was used. The AutoDockTools 1.5.6 and LigandScout 4.4.3 Advanced software were used to conduct the molecular docking simulation and pharmacophore screening, respectively, while the molecular dynamic simulation was performed using AMBER 16. The results were visualized by Biovia Discovery Studio. Results: Molecular docking using Autodock showed that FAT10 derivate has lower binding free energy (ΔG) (-12.04 kcal/mol) than AM (-8.45 kcal/mol) when docking to ERα and both performed the same hydrogen bond with Thr347. These support the results of the MMPBSA calculation on dynamic simulation which shows FAT10 (-58.4767 kcal/mol) has lower ΔG than AM (-42.7041 kcal/mol) and 4-OHT (- 49.0821 kcal/mol). The pharmacophore screening results also showed that FAT10 fitted the pharmacophore with a fit score of 47.08. Conclusion: From the results, it can be suggested that FAT10 has promising activity as ERα antagonist. Further in vitro and in vivo experiments should be carried out to support these in silico studies.

Background: Novel anti-tumor bioactivity compounds were designed by the strategy of modular hybridization with the bioactivity advantages of 5-fluorouracil and dithiocarbamate derivatives. Methods: A series of novel 5-fluorouracil-dithiocarbamate conjugates were synthesized, characterized and evaluated for their cytotoxic activities in vitro against B16, Hela and U87MG by MTT assay. Colonyformation, transwell migration, cell apoptosis and cell cycle distribution assays were performed to explore the anti-tumor activities and mechanism of conjugates for compounds P3 and P4. Conjugates, dithiocarbamate derivatives combined with copper ions and 5-fluorouracil were investigated by molecular docking. Results: The results of cytotoxicity assays illuminated that these conjugates had anti-tumor activity against B16, Hela and U87MG. Interestingly, the cytotoxicity of these conjugates was significantly increased when combined with copper ions, and compound P3 displayed better bioactivity compared to the other compounds. Conjugates might be metabolized in the cells to produce dithiocarbamates, and then metabolites formed complexes with copper ions, generating better anti-tumor effects. Molecular docking studies exhibited that compound P3 appeared the strongest interaction with the receptors 6CCY and 5T92. Conclusion: Compound P3 exhibited better anti-tumor bioactivity and might be emerged as the lead compound for the treatment of glioma. Further research in vivo will be performed in our following work.