Investigation of Cissus populnea as a Potential Therapeutic Agent for Erectile Dysfunction.

Cissus populnea (CP) is a plant reported to possess an erection-enhancing ability, though mechanisms remain unclear. Drugs targeting phosphodiesterase 5 (PDE5) inhibition, such as sildenafil, have been employed to treat erectile dysfunction (EDRF), but they are associated with several complications. This study investigated the effect of C. populnea extracts (aqueous and saponin-rich) on the activity and gene expressions of proteins related to erection. PDE5, Nitric oxide synthase (NOS) and androgen receptor (AR) genes were studied using RT-PCR on CP-treated paroxetine-induced ERDF-rats. It also employed Schrödinger suites for investigations such as molecular and induced-fit docking, MMGBSA, ADMET, and QSAR profiling of CP-phytocompounds. C. populnea extracts reduce the activity and downregulate the expression of the PDE5 gene while upregulating the expressions of AR and NOS genes in the ERDF-rats relative to the control group. Five (leading) compounds with induced-fit docking (IFD) scores in kcal/mol, namely, stigmasterol (-638.73), daucosterol (-644.73), furostanol (-639.29), papaverine (-639.03), and capsaicin (-642.88), had better docking scores of -9.936, -9.824, -9.064, -8.863, and -8.736 kcal/mol, respectively, compared with those of sildenafil (-8.611 kcal/mol). They also showed an excellent ADMET profile, satisfying Lipinski's rule of five. The MMGBSA predictions revealed that stigmasterol, daucosterol, papaverine, and capsaicin had binding free energies of -45.29, -59.14, -50.63, and -50.47 kcal/mol, respectively, suggesting that they are significant inhibitors of PDE5. The QSAR model revealed that lead compounds possess good pIC50 values. These results indicate that C. populnea is a more promising possible treatment for controlling EDRF and deserves further research.

The Nitrofuran-Warhead-Equipped Spirocyclic Azetidines Show Excellent Activity against Mycobacterium tuberculosis.

A series of 21 new 7'H-spiro[azetidine-3,5'-furo [3,4-d]pyrimidine]s substituted at the pyrimidine ring second position were synthesized. The compounds showed high antibacterial in vitro activity against M. tuberculosis. Two compounds had lower minimum inhibitory concentrations against Mtb (H37Rv strain) compared with isoniazid. The novel spirocyclic scaffold shows excellent properties for anti-tuberculosis drug development.

Time-series analysis of rhenium(I) organometallic covalent binding to a model protein for drug development.

Metal-based complexes with their unique chemical properties, including multiple oxidation states, radio-nuclear capabilities and various coordination geometries yield value as potential pharmaceuticals. Understanding the interactions between metals and biological systems will prove key for site-specific coordination of new metal-based lead compounds. This study merges the concepts of target coordination with fragment-based drug methodologies, supported by varying the anomalous scattering of rhenium along with infrared spectroscopy, and has identified rhenium metal sites bound covalently with two amino acid types within the model protein. A time-based series of lysozyme-rhenium-imidazole (HEWL-Re-Imi) crystals was analysed systematically over a span of 38 weeks. The main rhenium covalent coordination is observed at His15, Asp101 and Asp119. Weak (i.e. noncovalent) interactions are observed at other aspartic, asparagine, proline, tyrosine and tryptophan side chains. Detailed bond distance comparisons, including precision estimates, are reported, utilizing the diffraction precision index supplemented with small-molecule data from the Cambridge Structural Database. Key findings include changes in the protein structure induced at the rhenium metal binding site, not observed in similar metal-free structures. The binding sites are typically found along the solvent-channel-accessible protein surface. The three primary covalent metal binding sites are consistent throughout the time series, whereas binding to neighbouring amino acid residues changes through the time series. Co-crystallization was used, consistently yielding crystals four days after setup. After crystal formation, soaking of the compound into the crystal over 38 weeks is continued and explains these structural adjustments. It is the covalent bond stability at the three sites, their proximity to the solvent channel and the movement of residues to accommodate the metal that are important, and may prove useful for future radiopharmaceutical development including target modification.

Discovery of new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof.

New thymol-3,4-disubstitutedthiazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 6b, 6d, 6e, and 6f displayed in vitro inhibitory activity against COX-2 (IC50= 0.037, 0.042, 0.046, and 0.039 µM) nearly equal to celecoxib (IC50= 0.045 µM). 6b, 6d, and 6f showed SI (379, 341, and 374, respectively) higher than that of celecoxib (327). 6a-l elicited in vitro 5-LOX inhibitory activity higher than quercetin. 6a-f, 6i-l, 7a, and 7c possessed in vivo inhibition of formalin induced paw edoema higher than celecoxib. 6a, 6b, 6f, 6h-l, and 7b showed gastrointestinal safety profile as celecoxib and diclofenac sodium in the population of fasted rats. Induced fit docking and molecular dynamics simulation predicted good fitting of 6b and 6f without changing the packing and globularity of the apo protein. In conclusion, 6b and 6f achieved the target goal as multitarget inhibitors of inflammation.

Benzimidazoles Containing Piperazine Skeleton at C-2 Position as Promising Tubulin Modulators with Anthelmintic and Antineoplastic Activity.

Benzimidazole anthelmintic drugs hold promise for repurposing as cancer treatments due to their interference with tubulin polymerization and depolymerization, manifesting anticancer properties. We explored the potential of benzimidazole compounds with a piperazine fragment at C-2 as tubulin-targeting agents. In particular, we assessed their anthelmintic activity against isolated Trichinella spiralis muscle larvae and their effects on glioblastoma (U-87 MG) and breast cancer (MDA-MB-231) cell lines. Compound 7c demonstrated exceptional anthelmintic efficacy, achieving a 92.7% reduction in parasite activity at 100 µg/mL after 48 hours. In vitro cytotoxicity analysis of MDA-MB 231 and U87 MG cell lines showed that derivatives 7b, 7d, and 7c displayed lower IC50 values compared to albendazole (ABZ), the control. These piperazine benzimidazoles effectively reduced cell migration in both cell lines, with compound 7c exhibiting the most significant reduction, making it a promising candidate for further study. The binding mode of the most promising compound 7c, was determined using the induced fit docking-molecular dynamics (IFD-MD) approach. Regular docking and IFD were also employed for comparison. The IFD-MD analysis revealed that 7c binds to tubulin in a unique binding cavity near that of ABZ, but the benzimidazole ring was fitted much deeper into the binding pocket. Finally, the absolute free energy of perturbation technique was applied to evaluate the 7c binding affinity, further confirming the observed binding mode.

High-throughput virtual screening and molecular dynamics simulation reveals NPC170742 a novel chalconoid compound as a potential inhibitor of D-glycero-D-manno-heptose-1,7-bisphosphate 7-phosphatase in Helicobacter pylori.

Helicobacter pylori is a gram negative spiral shaped bacteria that causes peptic ulcer and gastric cancer. It Is the sixth most prevalent cancer in the world and the third leading cause of cancer death. The increase in reported cases of H. pylori resistance to the drugs and antibiotics shows the need for the development of new and efficient drugs against the pathogen. In the present study, D-glycero-D-manno-heptose-1,7-bisphosphate 7-phosphatase (GmhB), an enzyme involved in the biosynthesis of lipopolysaccharides that encourages bacterial adherence, self-aggregation and identifying the host cells was modelled and the active sites were predicted through POCASA which is an automated ligand binding site prediction server. Natural product activity and species source (NPASS) is a database of 96,481 natural compounds that were subjected to virtual screening workflow that includes Qikprop, Lipinski rule, filtering out reactive functional groups followed by high throughput virtual screening and the top 10 compounds were selected for further induced fit docking along with the substrate D-glycero-ß-D-manno-heptose 1,7-bisphosphate. The compound NPC170742 (Alpha, Beta, 3,4,5,2',4',6'-Octahydroxy dihydrochalcone) showed higher affinity than the substrate, and both the substrate D-glycero-ß-D-manno-heptose 1,7-bisphosphate and the compound NPC170742 were subjected to molecular dynamics simulation. The results exposed the compound NPC170742 could be a potential lead compound against the enzyme D-glycero-D-manno-heptose-1,7-bisphosphate 7-phosphatase of H. pylori.Communicated by Ramaswamy H. Sarma.

Architecture of the rings of 5-arylidenerhodanine derivatives versus P-gp inhibition.

5-Arylidene derivatives of rhodanine show various biological activities. The new crystal structures of five derivatives investigated towards ABCB1 efflux pump modulation are reported, namely, 2-[5-([1,1'-biphenyl]-4-ylmethylidene]-4-oxo-2-thioxothiazolidin-3-yl)acetic acid dimethyl sulfoxide monosolvate, C18H13NO3S2·C2H6OS (1), 4-[5-([1,1'-biphenyl]-4-ylmethylidene]-4-oxo-2-thioxothiazolidin-3-yl)butanoic acid, C20H17NO3S2 (2), 5-[4-(benzyloxy)benzylidene]-2-thioxothiazolidin-4-one, C17H13NO2S2 (3), 4-{5-[4-(benzyloxy)benzylidene]-4-oxo-2-thioxothiazolidin-3-yl}butanoic acid, C21H19NO4S2 (4), and 5-[4-(diphenylamino)benzylidene]-2-thioxothiazolidin-4-one, C22H16N2OS2 (5). Compounds 1 and 3-5 crystallize in the triclinic space group P-1, while 2 crystallizes in the monoclinic space group P21/n, where the biphenyl moiety is observed in two positions (A and B). Two molecules are present in the asymmetric unit of 5 and, for the other four compounds, there is only one molecule; moreover, 1 crystallizes with one dimethyl sulfoxide molecule. The packing of the molecules containing a carboxyl group (1, 2 and 4) is determined by O-H...O hydrogen bonds, while in the other two compounds (3 and 5), the packing is determined by N-H...O hydrogen bonds. Additionally, induced-fit docking studies have been performed for the active compounds to investigate their putative binding mode inside the human glycoprotein P (P-gp) binding pocket.

Virtual Screening Strategy and In Vitro Tests to Identify New Inhibitors of the Immunoproteasome.

Immunoproteasome inhibition is a promising strategy for the treatment of hematological malignancies, autoimmune diseases, and inflammatory diseases. The design of non-covalent inhibitors of the immunoproteasome ß1i/ß5i catalytic subunits could be a novel approach to avoid the drawbacks of the known covalent inhibitors, such as toxicity due to off-target binding. In this work, we report the biological evaluation of thirty-four compounds selected from a commercially available collection. These hit compounds are the outcomes of a virtual screening strategy including a dynamic pharmacophore modeling approach onto the ß1i subunit and a pharmacophore/docking approach onto the ß5i subunit. The computational studies were first followed by in vitro enzymatic assays at 100 µM. Only compounds capable of inhibiting the enzymatic activity by more than 50% were characterized in detail using Tian continuous assays, determining the dissociation constant (Ki) of the non-covalent complex where Ki is also the measure of the binding affinity. Seven out of thirty-four hits showed to inhibit ß1i and/or ß5i subunit. Compound 3 is the most active on the ß1i subunit with Ki = 11.84 ± 1.63 µM, and compound 17 showed Ki = 12.50 ± 0.77 µM on the ß5i subunit. Compound 2 showed inhibitory activity on both subunits (Ki = 12.53 ± 0.18 and Ki = 31.95 ± 0.81 on the ß1i subunit and ß5i subunit, respectively). The induced fit docking analysis revealed interactions with Thr1 and Phe31 of ß1i subunit and that represent new key residues as reported in our previous work. Onto ß5i subunit, it interacts with the key residues Thr1, Thr21, and Tyr169. This last hit compound identified represents an interesting starting point for further optimization of ß1i/ß5i dual inhibitors of the immunoproteasome.

Design, synthesis, molecular docking study and molecular dynamics simulation of new coumarin-pyrimidine hybrid compounds having anticancer and antidiabetic activity.

Coumarin-pyrimidine hybrid compounds were synthesized by condensation reaction of α,ß-unsaturated ketones of 6-acetyl-5-hydroxy-4-methylcoumarin with guanidine. The reaction yields were of 42-62%. The antidiabetic and anticancer activities of these compounds were examined. These compounds displayed low toxicity to two cancer cell lines (including KB and HepG2 ones), but exhibited remarkably active against α-amylase with IC50 values of 102.32 ± 1.15 µM to 249.52 ± 1.14 µM and against α-glucosidase with IC50 values of 52.16 ± 1.12 µM to 184.52 ± 1.15 µM. Amongst these compounds, 6c was the best inhibitory activity against α-amylase, and 6f had the highest activity against α-glucosidase. The kinetics of inhibitor 6f was competitive α-glucosidase inhibitor property. ADMET predictions showed that almost all synthesized compounds exhibited drug-like activity. IFD and MD simulations were carried out on enzymes 4W93 and 5NN8 to elucidate inhibitory potential of 6c and 6f against tested enzymes. The binding free energy calculation by MM-GBSA approach showed that Coulomb, lipophilic and van der Waals energy terms are major contributors for the inhibitor binding. Molecular dynamics simulations in water solvent system were carried out for the 6f/5NN8 complex to elucidate the variability of active interactions between ligand 6f and active pockets of this enzyme.

Synthesis, Molecular Modeling and Biological Evaluation of Novel Trifluoromethyl Benzamides as Promising CETP Inhibitors.

BACKGROUND: Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis. OBJECTIVE: Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher HDL and lower LDL levels. METHODS: Synthesis of nine benzylamino benzamides 8a-8f and 9a-9c was performed. RESULTS: In vitro biological study displayed potential CETP inhibitory activity, where compound 9c had the best activity with an IC50 of 1.03 µM. Induced-fit docking demonstrated that 8a-8f and 9a-9c accommodated the CETP active site and hydrophobic interaction predominated ligand/ CETP complex formation. CONCLUSION: Pharmacophore mapping showed that this scaffold endorsed CETP inhibitors features and consequently elaborated the high CETP binding affinity.

Tuning the Biological Activity of PI3Kδ Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow.

As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3Kδ) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity. In this paper, we compare and evaluate the accuracy of our previously described and validated in silico workflow with that of the standard (rigid) molecular docking approach. The findings demonstrated that a properly fitted catalytic (binding) pocket for our chemical cores at the induced-fit docking (IFD) and molecular dynamics (MD) stages, along with QM-derived atomic charges, can be used for activity prediction to better distinguish between active and inactive molecules. Moreover, the standard approach seems to be insufficient to score the halogenated derivatives due to the fixed atomic charges, which do not consider the response and indictive effects caused by fluorine. The proposed computational workflow provides a computational tool for the rational design of novel halogenated drugs.

Mitigating hERG Liability of Toll-Like Receptor 9 and 7 Antagonists through Structure-Based Design.

hERG is considered to be a primary anti-target in the drug development process, as the K+ channel encoded by hERG plays an important role in cardiac re-polarization. It is desirable to address the hERG safety liability during early-stage development to avoid the expenses of validating leads that will eventually fail at a later stage. We have previously reported the development of highly potent quinazoline-based TLR7 and TLR9 antagonists for possible application against autoimmune disease. Initial experimental hERG assessment showed that most of the lead TLR7 and TLR9 antagonists suffer from hERG liability rendering them ineffective for further development. The present study herein describes a coordinated strategy to integrate the understanding from structure-based protein-ligand interaction to develop non- hERG binders with IC50 >30 µM with retention of TLR7/9 antagonism through a single point change in the scaffold. This structure-guided strategy can serve as a prototype for abolishing hERG liability during lead optimization.

Isomeric Activity Cliffs-A Case Study for Fluorine Substitution of Aminergic G Protein-Coupled Receptor Ligands.

Currently, G protein-coupled receptors (GPCRs) constitute a significant group of membrane-bound receptors representing more than 30% of therapeutic targets. Fluorine is commonly used in designing highly active biological compounds, as evidenced by the steadily increasing number of drugs by the Food and Drug Administration (FDA). Herein, we identified and analyzed 898 target-based F-containing isomeric analog sets for SAR analysis in the ChEMBL database-FiSAR sets active against 33 different aminergic GPCRs comprising a total of 2163 fluorinated (1201 unique) compounds. We found 30 FiSAR sets contain activity cliffs (ACs), defined as pairs of structurally similar compounds showing significant differences in affinity (≥50-fold change), where the change of fluorine position may lead up to a 1300-fold change in potency. The analysis of matched molecular pair (MMP) networks indicated that the fluorination of aromatic rings showed no clear trend toward a positive or negative effect on affinity. Additionally, we propose an in silico workflow (including induced-fit docking, molecular dynamics, quantum polarized ligand docking, and binding free energy calculations based on the Generalized-Born Surface-Area (GBSA) model) to score the fluorine positions in the molecule.

Identifying Dopamine D3 Receptor Ligands through Virtual Screening and Exploring the Binding Modes of Hit Compounds.

The dopamine D3 receptor (D3R) is an important central nervous system target for treating various neurological diseases. D3R antagonists modulate the improvement of psychostimulant addiction and relapse, while D3R agonists can enhance the response to dopaminergic stimulation and have potential applications in treating Parkinson's disease, which highlights the importance of identifying novel D3R ligands. Therefore, we performed auto dock Vina-based virtual screening and D3R-binding-affinity assays to identify human D3R ligands with diverse structures. All molecules in the ChemDiv library (>1,500,000) were narrowed down to a final set of 37 molecules for the binding assays. Twenty-seven compounds exhibited over 50% inhibition of D3R at a concentration of 10 µM, and 23 compounds exhibited over 70% D3R inhibition at a concentration of 10 µM. Thirteen compounds exhibited over 80% inhibition of D3R at a concentration of 10 µM and the IC50 values were measured. The IC50 values of the five compounds with the highest D3R-inhibition rates ranged from 0.97 µM to 1.49 µM. These hit compounds exhibited good structural diversity, which prompted us to investigate their D3R-binding modes. After trial and error, we combined unbiased molecular dynamics simulation (MD) and molecular mechanics generalized Born surface area (MM/GBSA) binding free-energy calculations with the reported protein−ligand-binding pose prediction method using induced-fit docking (IFD) and binding pose metadynamics (BPMD) simulations into a self-consistent and computationally efficient method for predicting and verifying the binding poses of the hit ligands to D3R. Using this IFD-BPMD-MD-MM/GBSA method, we obtained more accurate and reliable D3R−ligand-binding poses than were obtained using the reported IFD-BPMD method. This IFD-BPMD-MD-MM/GBSA method provides a novel paradigm and reference for predicting and validating other protein−ligand binding poses.

Multi-Targeting Approach in Selection of Potential Molecule for COVID-19 Treatment.

The coronavirus disease (COVID-19) is a pandemic that started in the City of Wuhan, Hubei Province, China, caused by the spread of coronavirus (SARS-CoV-2). Drug discovery teams around the globe are in a race to develop a medicine for its management. It takes time for a novel molecule to enter the market, and the ideal way is to exploit the already approved drugs and repurpose them therapeutically. We have attempted to screen selected molecules with an affinity towards multiple protein targets in COVID-19 using the Schrödinger suit for in silico predictions. The proteins selected were angiotensin-converting enzyme-2 (ACE2), main protease (MPro), and spike protein. The molecular docking, prime MM-GBSA, induced-fit docking (IFD), and molecular dynamics (MD) simulations were used to identify the most suitable molecule that forms a stable interaction with the selected viral proteins. The ligand-binding stability for the proteins PDB-IDs 1ZV8 (spike protein), 5R82 (Mpro), and 6M1D (ACE2), was in the order of nintedanib > quercetin, nintedanib > darunavir, nintedanib > baricitinib, respectively. The MM-GBSA, IFD, and MD simulation studies imply that the drug nintedanib has the highest binding stability among the shortlisted. Nintedanib, primarily used for idiopathic pulmonary fibrosis, can be considered for repurposing for us against COVID-19.

Trifluoromethylated Aryl Sulfonamides as Novel CETP Inhibitors: Synthesis, Induced Fit Docking, Pharmacophore Mapping and Subsequent In vitro Validation.

BACKGROUND: Cardiovascular disease is one of the leading causes of death. Atherosclerosis causes arterial constriction or obstruction, resulting in acute cardiovascular illness. Cholesteryl ester transfer protein (CETP) facilitates reverse cholesterol transport. It supports the transfer of cholesteryl ester from HDL to LDL and VLDL. Inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL. OBJECTIVES: In this study, fourteen trifluoromethyl substituted benzene sulfonamides 6a-6g and 7a-7g were prepared. METHODS: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR and HR-MS. They were in vitro tested to estimate their CETP inhibitory activity. RESULTS: In vitro biological evaluation showed that compounds 7d-7f had the highest inhibitory activity with 100% inhibition, while the inhibition observed by compounds 6a-6g, 7a-7c and 7g ranged from 2%-72% at 10 µM concentration. It was found that the addition of a fourth aromatic ring significantly improved the activity, which may be due to the hydrophobic nature of CETP. Also, the presence of ortho-chloro, meta-chloro and para-methyl substituents results in high inhibitory activity. CONCLUSION: The induced fit docking studies revealed that hydrophobic interaction guided ligand/ CETP binding interaction in addition to H-bond formation with Q199, R201, and H232. Furthermore, pharmacophore mapping demonstrated that this series satisfies the functionalities of the current CETP inhibitors.

Descriptor-free QSAR: effectiveness in screening for putative inhibitors of FGFR1.

The long short-term memory (LSTM) algorithm has provided solutions to the limitations of the descriptors-utilizing QSAR models in drug design. However, the direct application of LSTM remains scarce. The effectiveness of a descriptor-free QSAR (LSTM-SM) in modeling the FGFR1 inhibitors dataset while comparing with two conventional QSAR using descriptors (126 bits Morgan fingerprint and 2 D descriptors respectively) as a baseline model was investigated in this study. The validated descriptor-free QSAR model was thereafter used to screen for active FGFR1 inhibitors in the ChemDiv database and subjected to molecular docking, induced-fit docking, QM-MM optimization, and molecular dynamics simulations to filter for compounds with high binding affinity and suggest the putative mechanism of inhibition and specificity. The LSTM-SM model performed better than conventional QSAR; having accuracy, specificity, and sensitivity of 0.92, model loss of 0.025, and AUC of 0.95. Fifteen thousand compounds were predicted as actives from the ChemDiv database and four compounds were finally selected. Of the four, two showed putatively effective binding interactions with key active site residues. Molecular dynamics simulations on these compounds in complex with the receptor further give insight into the conformational dynamics of each compound bounded to the receptor. The complexes formed are stable and exhibit a similar degree of compactness. Our findings predicted the advent of self-feature extracting machine learning algorithms of compounds, and have provided the possibility of better predictive model quality that is not necessarily limited by compound descriptors. The putative FGFR1 inhibitors, with their mechanism of inhibition and specificity, were elucidated using this approachCommunicated by Ramaswamy H. Sarma.

A new series of thiazole-hydrazone hybrids for Akt-targeted therapy of non-small cell lung cancer.

In an attempt to identify potent antitumor agents for the fight against non-small cell lung cancer, new thiazolyl hydrazones (2a-n) were synthesized and examined for their in vitro cytotoxic effects on A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells by means of the MTT assay. Furthermore, the effects of the most potent anticancer agents on apoptosis and Akt inhibition were investigated. 2-[2-((Isoquinolin-5-yl)methylene)hydrazinyl]-4-(4-methylsulfonylphenyl)thiazole (2k) (IC50 = 1.43 ± 0.12 µM) and 2-[2-((isoquinolin-5-yl)methylene)hydrazinyl]-4-(1,3-benzodioxol-5-yl)thiazole (2l) (IC50 = 1.75 ± 0.07 µM) displayed more pronounced anticancer activity than cisplatin (IC50 = 3.90 ± 0.10 µM) on A549 cell lines; 2-[2-((isoquinolin-5-yl)methylene)hydrazinyl]-4-(4-methoxyphenyl)thiazole (2j) (IC50 = 3.93 ± 0.06 µM) showed anticancer activity close to cisplatin. These compounds were found to induce apoptosis in A549 cells. Compound 2j (IC50 = 3.55 ± 0.64 µM) showed stronger Akt inhibitory activity than GSK690693 (IC50 = 4.93 ± 0.06 µM), while compounds 2k and 2l did not cause Akt inhibition at IC50 concentrations (1.43 and 1.75 µM, respectively). To comprehensively elucidate the binding pose of compound 2j and to provide a detailed understanding on the ligand' binding mechanism, induced-fit docking calculations were also conducted. Both in vitro and in silico studies suggest that compound 2j shows its cytotoxic and apoptotic effects on A549 cell lines via Akt inhibition. However, it is understood that compounds 2k and 2l exert their strong anticancer effects on A549 cells through different pathways.

Structural Features Affecting the Interactions and Transportability of LAT1-Targeted Phenylalanine Drug Conjugates.

L-type amino acid transporter 1 (LAT1) transfers essential amino acids across cell membranes. Owing to its predominant expression in the blood-brain barrier and tumor cells, LAT1 has been exploited for drug delivery and targeting to the central nervous system (CNS) and various cancers. Although the interactions of amino acids and their mimicking compounds with LAT1 have been extensively investigated, the specific structural features for an optimal drug scaffold have not yet been determined. Here, we evaluated a series of LAT1-targeted drug-phenylalanine conjugates (ligands) by determining their uptake rates by in vitro studies and investigating their interaction with LAT1 via induced-fit docking. Combining the experimental and computational data, we concluded that although LAT1 can accommodate various types of structures, smaller compounds are preferred. As the ligand size increased, its flexibility became more crucial in determining the compound's transportability and interactions. Compounds with linear or planar structures exhibited reduced uptake; those with rigid lipophilic structures lacked interactions and likely utilized other transport mechanisms for cellular entry. Introducing polar groups between aromatic structures enhanced interactions. Interestingly, compounds with a carbamate bond in the aromatic ring's para-position displayed very good transport efficiencies for the larger compounds. Compared to the ester bond, the corresponding amide bond had superior hydrogen bond acceptor properties and increased interactions. A reverse amide bond was less favorable than a direct amide bond for interactions with LAT1. The present information can be applied broadly to design appropriate CNS or antineoplastic drug candidates with a prodrug strategy and to discover novel LAT1 inhibitors used either as direct or adjuvant cancer therapy.

Improved docking of peptides and small molecules in iMOLSDOCK.

iMOLSDOCK is an induced-fit docking algorithm that uses the mutually orthogonal Latin squares (MOLS) sampling technique. Here, we describe the updates made to iMOLSDOCK in order to increase receptor flexibility, improve the scoring system, and speed up calculation. With a dataset of 35 peptide-protein complexes, the PepSet benchmark dataset of 80 peptide-protein complexes, and the Astex Diverse set, which uses nonpeptide small molecules as ligands, iMOLSDOCK has been benchmarked and validated. Flexible residues are now able to deviate from the starting position by a maximum of 3.0 Å due to the increased receptor flexibility. The ranking effectiveness of iMOLSDOCK has increased by 24% once the scoring system was improved. Additionally, iMOLSDOCK has been compared to Gold v5.2.1, HPEPDOCK, AutoDock CrankPep v1.0, AutoDock Vina, HADDOCK, PatchDock, and RosettaLigand. For induced-fit peptide-protein docking, iMOLSDOCK achieved success rates of 6%, 37%, and 89% at the top 1, 10, and 100 levels. At the top 1, 10, and 100 levels, iMOLSDOCK had success rates for small molecule-protein docking of 14%, 31%, and 49%. The computation time for peptide docking was lowered by two orders of magnitude, and for nonpeptide small molecule docking, it was roughly 14 times faster due to code optimization in the iMOLSDOCK docking tool. Source code and binary of iMOLSDOCK could be obtained from https://sourceforge.net/projects/mols2-0/files/ .