Letters in Drug Design & Discovery - Volume 19, Issue 7, 2022

Tetramethylpyrazine (TMP), or ligustrazine, is an alkaloid isolated from the Chinese herb Ligusticum wallichii. It is known for its broad-spectrum medicinal properties against several diseases, and various studies have shown that it can modulate diverse biological targets and signaling pathways to produce neuroprotective effects, especially against Alzheimer’s disease (AD). This has attracted significant research attention evaluating TMP as a potent multitarget anti-AD agent. This review compiles the results of studies assessing the neuroprotective mechanisms exerted by TMP as well as its derivatives prepared using a multi-target-directed ligand strategy to explore its multitarget modulating properties. The present review also highlights the work done on the design, synthesis, structure-activity relationships, and mechanisms of some potent TMP derivatives that have shown promising anti-AD activities. These derivatives were designed, synthesized, and evaluated to develop anti-AD molecules with enhanced biological and pharmacokinetic activities compared to TMP. This review article paves the way for the exploration and development of TMP and TMP derivatives as an effective treatment for AD.

Aims: The aim of this work is to investigate the antioxidant and anti-inflammatory potency of novel gabapentin derivatives, which could be proven useful as neuroprotective agents. Background: Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders worldwide. Due to its multi-factorial character, no effective treatment has been obtained yet. In this direction, the multi-targeting compounds approach could be useful for the development of novel, more effective drugs against AD. Oxidative stress and inflammation are highly involved in the progression of neurodegeneration, while gabapentin has been investigated for the treatment of behavioral symptoms in AD. Objective: In this work, derivatives of cinnamic acid, Trolox, and 3,5-di-tertbutyl-4-hydroxybenzoic acid amidated with gabapentin methyl ester were designed and studied. Compounds with these structural characteristics are expected to act in various biochemical pathways, affecting neurodegenerative processes. Methods: The designed compounds were synthesized with classical amidation methods, purified by flash column chromatography, and identified spectrometrically (¹H-NMR and ¹³C-NMR). Their purity was determined by CHN elemental analysis. They were tested in vitro for their antioxidant and antiinflammatory properties and for their inhibitory effect on acetylcholinesterase. Their in vivo antiinflammatory activity was also tested. Results: Molecules that incorporated antioxidant moiety possessed inhibitory activity against rat microsomal membrane lipid peroxidation and oxidative protein glycation, as well as radical scavenging activity. Moreover, most of them presented moderate inhibition towards lipoxygenase (up to 51% at 100μ) and acetylcholinesterase (AchE) (IC50 up to 274μ) activities. Finally, all synthesized compounds presented in vivo anti-inflammatory activity, decreasing carrageenan-induced rat paw edema up to 53%, and some of them could inhibit cyclooxygenase significantly. Conclusion: These results indicate that the designed compounds could be proven useful as multitargeting molecules against AD since they affect various biochemical pathways associated with neurodegeneration. Thus, more effective drugs can be obtained, and the possible adverse effects of drug combinations can be limited.

Background: Protein kinase B (Akt) is a serine/threonine-protein kinase that drives the diverse physiological process. Akt is a promising therapeutic target, which involves cancer cell growth, survival, proliferation and metabolism. Objective: The study aims to design highly active Akt inhibitors, and to elucidate the structural requirements for their biological activity, we analyzed the key binding features and summarized the structural determinants for their bioactivities. Methods: A series of piperidine derivatives have been investigated employing three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulation. Results: The statistics of the comparative molecular field analysis (CoMFA) model (Q²=0.631, R²=0.951) and the comparative molecular similarity index analysis (CoMSIA) model (Q²=0.663, R²=0.966) indicated that our 3D-QSAR model was accurate and reliable. Besides, the stability of receptor-ligand interactions under physiological conditions was then evaluated by molecular dynamics simulation, in agreement with the molecular docking results. Conclusion: Our study provided valuable insights for the discovery of potent Akt inhibitors.

Background: Boesenbergia pandurata or fingerroot is known to have various pharmacological activities, including anticancer properties. Extracts from these plants are known to inhibit the growth of cancer cells, including breast cancer. Anti-breast cancer activity is significantly influenced by the inhibition of two receptors: ER-α and HER2. However, it is unknown which metabolites of B. pandurata play the most crucial role in exerting anticancer activity. Objective: This study aimed to determine the metabolites of B. pandurata with the best potential as ER-α and HER2 inhibitors. Methods: The method used was molecular docking of several B. pandurata metabolites to ER-α and HER2 receptors, followed by an ADMET study of several metabolites with the best docking results. Results: The docking results showed eight metabolites with the best docking results for the two receptors based on the docking score and ligand-receptor interactions. Of these eight compounds, compounds 11 ((2S)-7,8-dihydro-5-hydroxy-2-methyl-2-(4''-methyl-3''-pentenyl)-8-phenyl-2H,6H-benzo(1,2-b-5,4- b')dipyran-6-one) and 34 (geranyl-2,4-dihydroxy-6-phenethylbenzoate) showed the potential to inhibit both receptors. Both ADMET profiles also showed mixed results; however, there is a possibility of further development. Conclusion: In conclusion, the metabolites of B. pandurata, especially compounds 11 and 34, can be developed as anti-breast cancer agents by inhibiting ER-α and HER2.

Aims: This study aims to investigate and validate the potential drug target to HDAC1. Background: Human histone deacetylase 1 (HDAC1) can catalyze the deacetylation of histones belonging to the family of human histone deacetylases (HDACs). Amide hydrolase HDAC1 plays a key role in the development of many serious cancers such as prostate cancer, gastric cancer, lung cancer, esophageal cancer, colon cancer, and breast cancer. Therefore, HDAC1 inhibitors, promoting the transcription of a series of key genes such as the p53 gene and inhibiting the development of cancer through various downstream mechanisms, have great potential for the treatment of cancer. Objective: The objective of this study is to discover new skeleton HDAC1 inhibitors efficiently and conveniently with therapeutic potential for cancer. Methods: Based on the crystal structure of HDAC1, through the combination of receptor-based and ligand- based virtual screening from the commercial compound library, the top-ranked compounds are selected for purchase through binding modes analysis, and their activities were verified through in vitro HDAC1 inhibitory biological experiments. Results: Based on LeDock, 5ICN showed good distinguishing ability and was used as the receptor. According to the results of the LeDock docking scoring from receptor-based virtual screening, 69 compounds with binding energy less than -7.5 kcal/mol were obtained and used for ligand-based virtual screening. A total of 21 novel compounds with high potential HDAC1 inhibitory activity were collected by combining the similarity searching (NN) and the multinomial Naive Bayes machine learning model (NB) methods. Through binding modes analysis, 10 compounds with different structures with potential HDAC1 inhibitory activity were selected and screened HDAC1 inhibitory in vitro. May267 showed moderate HDAC1 inhibitory activity, and the inhibition rate was 48% at a concentration of 20 μM. Conclusion: This study discovers novel small molecule HDAC1 inhibitors by combined receptor-based and ligand-based virtual screening strategy, which provides an efficient method for the discovery of other small molecule drugs. May267 shows moderate HDAC1 inhibitory activity, which can be further optimized as a lead compound. However, it still has the problem of poor kinase selectivity to be solved.

Background: Since the end of 2019, the etiologic agent SAR-CoV-2 responsible for one of the most significant epidemics in history has caused severe global economic, social, and health damages. The drug repurposing approach and application of Structure-based Drug Discovery (SBDD) using in silico techniques are increasingly frequent, leading to the identification of several molecules that may represent promising potential. Methods: In this context, here we use in silico methods of virtual screening (VS), pharmacophore modeling (PM), and fragment-based drug design (FBDD), in addition to molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM -PBSA) calculations, and covalent docking (CD) for the identification of potential treatments against SARS-CoV-2. We initially validated the docking protocol followed by VS in 1,613 FDA-approved drugs obtained from the ZINC database. Thus, we identified 15 top hits, of which three of them were selected for further simulations. In parallel, for the compounds with a fit score value ≤ of 30, we performed the FBDD protocol, where we designed 12 compounds. Results: By applying a PM protocol in the ZINC database, we identified three promising drug candidates. Then, the 9 top hits were evaluated in simulations of MD, MM-PBSA, and CD. Subsequently, MD showed that all identified hits showed stability at the active site without significant changes in the protein's structural integrity, as evidenced by the RMSD, RMSF, Rg, SASA graphics. They also showed interactions with the catalytic dyad (His⁴¹ and Cys¹⁴⁵) and other essential residues for activity (Glu¹⁶⁶ and Gln¹⁸⁹) and high affinity for MM-PBSA, with possible covalent inhibition mechanism. Conclusion: Finally, our protocol helped identify potential compounds wherein ZINC896717 (Zafirlukast), ZINC1546066 (Erlotinib), and ZINC1554274 (Rilpivirine) were more promising and could be explored in vitro, in vivo, and clinical trials to prove their potential as antiviral agents.

Background: The 1,4-naphthoquinone ring has attracted prominent interest in the field of medicinal chemistry due to its potent pharmacological activities such as antioxidant, antibacterial, antifungal, and anticancer. Objectives: Herein, a series of new Schiff bases (4-6) and chalcones (8a-c & 9a-d) bearing 1,4- naphthoquinone moiety were synthesized in good yields and were subjected to in-vitro antimicrobial, antioxidant, and molecular docking testing. Methods: A facile protocol has been described in this study for the synthesis of new derivatives (4-7, 8ac, and 9a-d) bearing 1,4-naphthoquinone moiety. The chemical structures of all the synthesized compounds were identified by ¹H-NMR, ¹³C-NMR, MS, and elemental analyses. Moreover, these derivatives were assessed for their in-vitro antimicrobial activity against gram-positive, gram-negative bacteria, and fungal strains. Further studies were conducted to test their antioxidant activity using DPPH (2,2-diphenyl- 1-picrylhydrazyl) scavenging assay. Molecular docking studies were realized to identify the most likely interactions of the novel compounds within the protein receptor. Results: The antimicrobial results showed that most of the compounds displayed good efficacy against both bacterial and fungal strains. The antioxidant study revealed that compounds 9d, 9a, 9b, 8c, and 6 exhibited the highest radical scavenging activity. Docking studies of the most active antimicrobial compounds within GLN- 6-P, recorded good scores with several binding interactions with the active sites. Conclusion: Based on the obtained results, it was found that compounds 8b, 9b, and 9c displayed the highest activity against both bacterial and fungal strains. The obtained findings from the DPPH radical scavenging method revealed that compounds 9d and 9a exhibited the strongest scavenging potential. The molecular docking studies proved that the most active antimicrobial compounds 8b, 9b and 9c displayed the highest energy binding scores within the glucosamine-6-phosphate synthase (GlcN-6-P) active site.