Letters in Drug Design & Discovery - Volume 21, Issue 16, 2024

The High-density lipoprotein (HDL) receptor, Scavenger receptor class B, type I (SRBI) plays a crucial role in lipoprotein metabolism, cholesterol homeostasis, and atherosclerosis. In the present study, a quantitative structure-activity relationship study (QSAR) investigation was conducted on a data set of 31 novel indolinyl thiazole-based inhibitors of SR-BI mediated lipid uptake.

To build the QSAR model, Multiple linear regression analysis (MLR), partial least square analysis (PLS), and neural analysis (NN) were performed which were further evaluated internally as well as externally for the prediction of activity. The best QSAR model for MLR was selected with a correlation coefficient (r2) of 0.937, cross-validation r2cv of 0.908, and a standard error (S) value of 0.253. For PLS, r2 was 0.937 and for FFNN r2 was 0.961 (for the training set). This was further evaluated externally by a test set having r2 values 0.870 (MLR), 0.863(PLS), and 0.933(neural network) analysis.

The final model comprised hydrophobic parameters (Lipole Z component) and steric parameters (molar refractivity and K alpha2 index).

All these descriptors generated comparable results which prove that the model generated is sound and has good predictability.

This study aimed to design and synthesize a series of novel C8-Formononetin derivatives and evaluate their in vitro anti-tumor activity. The experimental results showed that these derivatives exhibited varying degrees of anti-tumor effects on HeLa, A549, and HepG2 cells, and compound 8, in particular, showed excellent inhibitory activity against HepG2 cell growth, which surpassed that of 5-FU.

Importantly, the cytotoxicity of FMN was significantly enhanced after conjugation with amino acid ethyl ester. To further investigate the mechanisms underlying the anti-tumor effects of these derivatives, various experimental approaches were employed. They include colony formation assay, EdU cell proliferation assay, Transwell migration assay, cell apoptosis assay, cell cycle distribution assay, and ELISA.

The results revealed that compound 8 effectively induced cell apoptosis by downregulating the expression of anti-apoptotic proteins P53, Bcl-2, and Mcl-1 while upregulating the expression of pro-apoptotic proteins Bax, Fas, Caspase-3, Caspase-9, and Fas, which leads to apoptosis of tumor cells. Furthermore, compound 8 disrupted the mitochondrial membrane potential, perturbed cellular energy metabolism, and reduced intracellular ATP levels, thereby inhibiting tumor cell growth.

The newly synthesized FMN derivatives in this study hold great potential in the field of anti-tumor research. Compound 8 inhibits tumor cell growth through multiple pathways, which provides new hope for cancer treatment.

PDE5 inhibitors have had a surge in popularity over the last decade owing to their efficacy in the treatment of erectile dysfunction, coronary vasculopathy, and pulmonary arterial hypertension. These inhibitors exhibit competitive binding with phosphodiesterase type 5 and inhibit the hydrolysis of cyclic guanosine monophosphate, hence elevating the levels of cGMP in smooth muscle cells and prolonging the duration of an erection. However, due to production costs and side effects, further research is needed to discover new PDE5 inhibitors.

The study aimed to identify potent PDE5 inhibitors by employing the extensive application of computer-aided drug design.

Three different databases, named Million Molecules Database, Natural Product Database, and NCI Database, have been screened, which has been followed by filtering based on various drug-likeness rules, docking, ADME, toxicity, consensus molecular docking, and 100 ns molecular dynamics simulation.

Three compounds (ZINC05351336, ZINC12030898, and ZINC17949426) have exhibited stable-binding characteristics at the active site of PDE5, demonstrating a robust binding affinity. These molecules have been found to possess drug-like capabilities, effective ADME features, low toxicity, and high stability.

The study has delved into the realm of PDE5 inhibitors, which have been found to be effective in treating erectile dysfunction, but high production costs and side effects necessitate new ones. Through computer-aided drug design and screening, three compounds have been identified with promising binding characteristics, drug-appropriate properties, effective ADME profiles, minimal toxicity, and stability, making them potential candidates for future PDE5 inhibitors.

A series of 2-arylbenzimidazole derivatives were designed and developed as antidiabetic drugs using 2D and 3D QSAR, molecular docking and ADME studies.

All molecular modeling studies were performed using Molecular Design Suite V-Life MDS software. New chemical entities (NCEs) were designed based on the results of 2D and 3D QSAR studies. Docking studies were performed with the designed NCEs in PDB: 5E0F and the results were compared with the receptor ligand. According to the ADME results, all the proposed compounds have good oral absorption, correct molecular weight, QPlogPo/w. All units show oral absorption above 80%, it is considered well absorbed. All the proposed units show satisfactory results in the area. This indicated that these NCEs have little or no chance of failure in the final stages of the drug development process.

The 2D QSAR results showed that the descriptor k2alpha, T_T_N_5, IodinesCount and BrominesCount play the most important role in determining the inhibitory activity of α-amylase. Although 3D QSAR showed that, the q² and Pred_r² values of the model (SA kNN MFA model) were 0.7476 and 0.6932. The G score of the proposed compound numbers mol-1, mol-2, mol-3, mol-4, mol-5, mol-6, mol-7 and mol-8 are better compared to the standards, indicating that the proposed compounds have good binding properties affinity to bind to α-amylase.

These investigations have produced statistically significant and exceptionally reliable 2D and 3D Quantitative Structure-Activity Relationship (QSAR) models for antidiabetic medications, particularly α-amylase inhibitors. Furthermore, docking experiments involving the α-amylase enzyme have revealed that the binding energies of most Novel Chemical Entities (NCEs) are comparable to those of the established standards. Docking studies with α-amylase enzyme showed that most NCEs have binding energies comparable to the standard.

Mcl-1 is a kind of antiapoptotic protein and its overexpression is closely related to the occurrence of cancer. Aryl sulfonamide derivatives are expected to become new anticancer agents due to their high inhibitory activity on the Mcl-1 protein.

The study aimed to establish the QSAR model with good prediction ability and elaborate the influence of structure and chirality on the inhibitory activity.

Multiple QSAR models were built with different types of descriptors and modeling methods. The molecular docking was performed on compounds 45, 25, 26, 24R, and 24S. The MCCV method was used to perform rigorous validations with up to 2¹⁶ = 65,536 samplings for MLR, SVM, LSSVM, RF, and GP methods based on the model of 2D and 3D combined descriptors.

The models based on 2D and 3D combined descriptors demonstrated non-linear LSSVM and GP methods to provide better results (R²>0.94, > 0.86). The predictive performances of MCCV tests have been basically coincident with the single test set’s results. The hydrogen bond acceptor at the appropriate position of the substituent on the chiral center could form the hydrogen bond interaction with residue ASN260, resulting in stronger interaction and higher inhibitory activity. The interaction differences between R and S configurations could be mainly attributed to two residues, HIS224 and ASN260. Furthermore, the steric effect of the substituent on chiral carbon atoms was crucial. A high steric effect could prevent the binding of the substituent and protein, resulting in low inhibitory activity.

The study may provide theoretical guidance on the design and synthesis of novel aryl sulfonamide derivatives with high inhibitory activity.

Inhibitors of topoisomerases, essential regulators of cancer development, are promising as cancer treatments. These enzymes regulate DNA topology and eliminate topological constraints during various biological processes, including replication, transcription, and recombination. Nature has continually offered scientists pathways to explore the development of new drugs. Indeed, since ancient times, various plant extracts have been utilized in treating multiple pathologies.

It’s intriguing to diversify the therapeutic classes of natural topoisomerase 1 inhibitors. We aimed to explore the relationship between the toxicity of certain medicinal plants in North Africa and their anti-topoisomerase 1 enzyme activity. This investigation aims to discover potentially valuable compounds for fighting cancer by inhibiting the Topo1 enzyme, enriching the anticancer therapeutic class.

This study has conducted a virtual screening of the African Natural Products Database to identify new scaffolds as topoisomerase 1 inhibitors. Molecular docking as a structure-based drug design approach was selected as one of the best approaches, and the complex code ID: 1K4T was used for this purpose.

The molecular docking of more than 5790 natural products extracted from this database was docked into the binding site of the above-cited complex using the Modlock optimizer and Moldock score as search and scoring function algorithms, respectively. The top-ranked compounds have been assessed, analyzed, and compared to Topotecan and Irinotecan as reference ligands and drugs.

Consequently, the seven natural products have shown a strong affinity to topoisomerase 1 and DNA. They establish a clear link between topoisomerase 1 inhibition and the anticancer activity of their corresponding plant extracts. Therefore, these hits are promising and serve as a base for further development of new topoisomerase 1 inhibitors.

Hypertension is one of the main causes of chronic kidney disease. Astragalus membranaceus (AM), an important traditional Chinese medicine for treating hypertensive nephropathy, has a complex composition that makes it challenging to explore its mechanism of action and limits its clinical application. This study aims to investigate the underlying mechanism of AM in treating hypertensive nephropathy.

We retrieved all the compound data of AM from the Traditional Chinese Medicine Systems Pharmacology database and screened out the active compounds and their target proteins. Then, a network of candidate compounds and target compounds of AM was constructed using Cytoscape software. Furthermore, hypertensive nephropathy-related genes from the DisGeNET and GeneCards databases were intersected with AM target proteins and hypertensive nephropathy-related genes to determine the potential targets of AM in treating hypertensive nephropathy. Finally, after performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, we conducted molecular docking to verify the interaction between the main active ingredients of AM and the core targets.

A total of 87 effective components of AM were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. According to the network of active compounds and their target proteins, 18 of the 20 effective compounds in AM could act on 210 proteins. Taking the intersection of 274 hypertensive nephropathy-related genes and AM target proteins, 49 potential targets of AM in treating hypertensive nephropathy were identified. Using the median degree value, we determined 25 core targets of AM in treating hypertensive nephropathy. GO enrichment analysis showed that the biological processes of AM on hypertensive nephropathy mainly focused on the inflammatory response, hypoxia response, angiogenesis, cell proliferation, and cell migration. KEGG pathway enrichment analysis mainly involved cancer pathways, the AGE-RAGE signaling pathway in diabetic complications, blood flow shear stress, and atherosclerosis. Molecular docking results showed that quercetin, kaempferol, and 7-O-methylisomucronulatol had strong binding activity with several target proteins and may exert protective effects by stabilizing the interaction between molecules through the intermolecular forces of hydrogen bonds.

This study reveals the targets of AM in treating hypertensive nephropathy using network pharmacology and molecular docking, providing new clues for developing novel drugs for hypertensive nephropathy and basic research development.

Prevalence of microbial resistance due to Metallo-β-lactamase (MBL) enzyme pose a serious threat to human life. MBLs depend on active site zinc for their hydrolytic activity; hence, the investigation of zinc chelators emerged as an attractive strategy for the development of potent MBL inhibitors.

To prove that such chelators selectively target MBLs, in the present investigation, novel cephalosporins based MBL inhibitors (Cef-MBLi) were designed as a conjugate of cephalosporins with a potent zinc binder 8-thioquinoline (8-TQ).

Cef-MBLi showed site specific release of conjugate only in the presence of a Verona-integron encoded metallo-β-lactamase 2 (VIM-2) bacterial enzyme through hydrolytic cleavage mechanism. A total of 6 (4a-e and 6f) New Chemical Entities (NCE’s) were prepared, characterized and subjected for in vitro study.

Among tested NCE’s, 4c showed potent MBL inhibitory activity against the VIM-2 enzyme.

^# ZRC communication no: 687

Candida albicans is the yeast that causes the fungal infection known as candidiasis. One of the standard methods for treating candida is the application of fluconazole. The low solubility of fluconazole in aqueous media is a big problem in the use of this agent. Novel drug delivery systems, such as microemulsions, could be applied to solve this problem. The main aim of this study was to perform statistical optimization of the formulation and physicochemical characterization of fluconazole microemulsion.

Optimization of the microemulsion formulation was done by using experimental design software, and then fluconazole was loaded onto the best formulation at a concentration of 1 % w/w. The physiochemistry of the microemulsion formulation was assessed by pH measurement, rheology measurement, simultaneous thermal analysis, and Scanning Electron Microscopy (SEM).

The two-level fractional factorial design application demonstrated the optimum formulation to consist of surfactant, co-surfactant, oil content, and water, comprising 58%, 27%, 10%, and 5% of the formulation, respectively. Desirable thermal mass was observed up to 150°C. The formulation was a non-Newtonian shear-thinning liquid in terms of viscosity, with a reported pH between 6.5-7.

Considerably stable, high-quality microemulsion formulations containing fluconazole are presented, which are applicable for antifungal skin candidiasis treatment in clinical trials.

Hedyotis diffusa Willd (HDW) is an herb that has been used empirically for treating cancer, and its antileukemic effect has been confirmed by laboratory evidence. This study aimed to explore the underlying mechanism by which HDW and its active compound exert effects on acute myeloid leukemia (AML) through in silico analyses combined with experimental validation.

The targets of the compounds were collected from the database and intersected with AML targets. Based on these data, a protein-protein interaction (PPI) network and compound-target (C-T) network were constructed, and KEGG enrichment analysis was performed. Topological analysis of the C-T network and PPI network was performed to screen for hub compounds and targets. Molecular dynamics simulations were conducted to test the binding mode and strength between the targets and the compounds at the molecular level. Cell viability, flow cytometry, ELISA, and Q-PCR were further used to evaluate the in silico results.

A total of 86 targets of 12 screened active compounds of HDW against AML were identified. According to topological analysis, tumor protein p53 (TP53) and signal transducer and activator of transcription 3 (STAT3) exhibited the highest degree of centrality (DC) in the PPI networks of HDW targets. Quercetin had a higher affinity for TP53 than for STAT3. Molecular dynamics simulations confirmed that the TP53-quercetin docked complex was stable with respect to the original TP53-ligand complex. The targets of HDW and quercetin against AML were significantly enriched in multiple biological processes, including the p53 signaling pathway and apoptosis. The results from the in vitro experiment confirmed that quercetin triggers apoptosis in the human AML cell line KG-1 through the p53 pathway protein.

This study outlines the multi-compound, multi-target, and multi-pathway mechanism by which HDW affects AML based on an in silico predictive model and further validates the antileukemic mechanism of the screened active compound in an in vitro model. This study provides a perspective for studying the antileukemic mechanism of HDW for further research.

The histone deacetylase family of proteins, which includes the sirtuins, participates in a wide range of cellular processes, and is intimately involved in neurodegenerative illnesses. The research on sirtuins has garnered a lot of interest. However, there are currently no effective therapeutic drugs.

In order to explore the potential inhibitors of SIRTs, we first screened four potential lead compounds of SIRT2 in Traditional Chinese Medicine (TCM) for nervous disease using the AutoDock Vina method. Then, with Molecular Dynamics (MD) simulation method, we discovered how these inhibitors from Traditional Chinese herbal medicines affect this protein at the atomic level.

We found hydrophobic interactions between inhibitors and SIRT2 to be crucial. The small molecules have been found to have strong effect on the residues in the zinc-binding domain, exhibiting relationship with the signaling pathway. Finally, based on the conformational characteristics and the MD properties of the four potential inhibitors in TCM, we have designed the new skeleton molecules according to the parameters of binding energy, fingerprint similarity, 3D similarity, and RO5, with AI method using MolAICal software.

We have proposed the candidate inhibitor of SIRT2. Our research has provided a new approach that can be used to explore potential inhibitors from TCM. This could potentially pave the way for the creation of effective medicines.

Although indazole derivatives are rare and may not be available easily in nature, there are many reports demonstrating their pharmaceutical and other applications.

This study aimed to synthesize new indazole derivatives and evaluate their anti-proliferative activity to produce new anti-cancer agents.

Compounds 3a-c were synthesized through the reaction. The 2-aryllidenecyclohexane-1,3-dione derivatives 3a-c were obtained through the reaction of cyclohexane-1,3-dione with aromatic aldehydes used for the synthesis of thieno-[3,2-e]indazole derivatives. These derivatives were characterized by extensive analytical and spectral studies and were further used as starting materials for some heterocyclic transformations to produce biologically active compounds. The antiproliferative activities of the newly synthesized compounds were evaluated against the six cancer cell lines, A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460. Most of the tested compounds exhibited high cytotoxicity except a few compounds.

In this study, new compounds were synthesized, characterized, and evaluated toward the selected six cancer cell lines. All tested compounds displayed potent c-Met enzymatic activity with IC50 values ranging from 0.25 to 10.30 nM and potent prostate PC-3 cell line inhibition with IC50 values ranging from 0.17 to 9.31 μM.

The results obtained in this work demonstrated that the variations in substituents within the aryl moiety, together with the attached heterocyclic ring, have a notable influence on the antiproliferative activity. The results obtained in this work encourage further work in the future.

Metastatic Castration-resistant Prostate Cancer (mCRPC) represents a critical challenge in current prostate cancer treatment. Benzimidazole Derivative XY123 has emerged as a novel inhibitor for its treatment.

This study aims to establish a robust Quantitative Structure-Activity Relationship (QSAR) model for predicting the activity of Benzimidazole Derivative XY123 derivatives, aiding the development of novel anti-prostate cancer drugs.

Utilizing CODESSA software, descriptors were computed based on various moieties of Benzimidazole Derivative XY123 derivatives. Multiple linear regression models were constructed, and both linear and nonlinear QSAR models were developed using heuristics and gene expression programming.

The linear model with two descriptors demonstrated the best predictive capacity for inhibitor activity, while the nonlinear model generated through Gene Expression Programming (GEP) exhibited correlation coefficients of 0.83 and 0.82 for the training and test sets, respectively. The average errors were 0.03 and 0.05, indicating the stability and the improved predictive ability of the nonlinear model.

The QSAR linear model has an advantage over the nonlinear model in optimizing Benzimidazole Derivative XY123, providing a direction for the development of effective drugs for mCRPC treatment.

Thirteen derivatives were designed and synthesized based on the excellent lead compound Matrine.

This study aimed to discover novel anticancer agents with superior anticancer activity and to support the discovery of new drugs.

The in vitro antiproliferative activity of all derivatives against four human cancer cells, A549, HGC-27, HCT-116, and HeLa, was determined by MTT. The best active compounds were subjected to cell cloning, migration, cell cycle and apoptosis, and molecular docking.

Compound 5XI showed the best activity against all four cell lines, especially against A549 cells, with an IC50 of 5.805 μmol/L. The antiproliferative activity of 5XI was much higher than that of matrine and only slightly weaker than that of Cisplatin, a multi-targeted small molecule inhibitor. 5XI also showed excellent inhibitory activity in cell cycle, apoptosis, cell scratch, and cell cloning assays and has shown good affinity in docking studies.

5XI has excellent antiproliferative activity, significantly inhibits cell cloning and migration, affects cancer cell cycle distribution, and induces apoptosis in a concentration-dependent manner, making it a potential anticancer drug agent.

Investigating the structural attributes of the murine beta3-adrenergic receptor (β3-AR) is imperative for comprehending metabolic regulation, given its close resemblance to the human β3-AR. This receptor holds promise as a target for novel drug development against obesity and diabetes. Despite its potential, the absence of knowledge regarding the structure of murine β3-AR hampers a comprehensive understanding of its functionality.

Our study aimed to model the three-dimensional (3D) structure of murine β3-AR through various molecular structure prediction and simulation techniques, thus addressing the existing gap in structural information.

Employing diverse structure prediction programs, we refined the predicted structure of murine β3-AR. Primary sequence analysis offered insights into charge distribution, stability, and hydrophobic properties. The binding sites were identified in the modeled structure. Molecular Dynamics (MD) simulation provided the structural stability and dynamic behavior of the predicted β3-AR structure.

The β3-AR protein exhibited specific characteristics, including a pI of 9.57, an aliphatic index of 98.35, a GRAVY score of 0.289, and the presence of conserved motifs and disulfide linkages. Utilizing the programs such as Phyre2, SWISS MODEL, I-Tasser, and AlphaFold2, we generated a 3D model of murine β3-AR. Subsequent refinement using ModRefiner revealed a structure comprising 13 helices, 2 strands, and 21 turns. The Ramachandran plot indicated favorable regions for 93.2% of residues, with minimal deviations. A 50 ns MD simulation demonstrated the consistent stability and integrity of the β3-AR protein. The top three binding pockets were identified based on varying areas and volumes. Dynamic behavior within residues Ser 252 and Arg 253 was observed, indicating flexibility in conformation. This study marks the first-ever exploration, offering initial structural insights into murine β3-AR.

This study underscores the critical role of computational approaches in predicting the 3D structure of β3-AR. We derived a refined model by employing diverse prediction techniques, elucidating key features. The findings emphasize the significance of this methodology in comprehending the structural foundation of β3-AR, providing valuable insights for targeted medication development against conditions such as obesity and diabetes.