Flexible ligand docking using a robust evolutionary algorithm

A flexible ligand docking protocol based on evolutionary algorithms is investigated. The proposed approach incorporates family competition and adaptive rules to integrate decreasing‐based mutations and self‐adaptive mutations to act as global and local search strategies, respectively. The method is applied to a dihydrofolate reductase enzyme with the anticancer drug methotrexate and two analogues of antibacterial drug trimethoprim. Conformations and orientations closed to the crystallographically determined structures are obtained, as well as alternative structures with low energy. Numerical results indicate that the new approach is very robust. The docked lowest‐energy structures have root‐mean‐square derivations ranging from 0.67 to 1.96 Å with respect to the corresponding crystal structures. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 988–998, 2000     

Design,Synthesis, Biological Evaluation,and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors

PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q² = 0.797 and r² = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q² = 0.567 and r² = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87).     

Solvent-Free Synthesis,In Vitro and In Silico Studies of Novel Potential 1,3,4-Thiadiazole-Based Molecules against Microbial Pathogens

A new series of 1,3,4-thiadiazoles was synthesized by the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate (2) with selected derivatives of hydrazonoyl halide by grinding method at room temperature. The chemical structures of the newly synthesized derivatives were resolved from correct spectral and microanalytical data. Moreover, all synthesized compounds were screened for their antimicrobial activities using Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Bacillus subtilis, Staphylococcus aureus, and Candida albicans. However, compounds 3 and 5 showed significant antimicrobial activity against all tested microorganisms. The other prepared compounds exhibited either only antimicrobial activity against Gram-positive bacteria like compounds 4 and 6, or only antifungal activity like compound 7. A molecular docking study of the compounds was performed against two important microbial enzymes: tyrosyl-tRNA synthetase (TyrRS) and N-myristoyl transferase (Nmt). The tested compounds showed variety in binding poses and interactions. However, compound 3 showed the best interactions in terms of number of hydrogen bonds, and the lowest affinity binding energy (−8.4 and −9.1 kcal/mol, respectively). From the in vitro and in silico studies, compound 3 is a good candidate for the next steps of the drug development process as an antimicrobial drug.     

QSAR Modeling,Molecular Docking and Cytotoxic Evaluation for Novel Oxidovanadium(IV) Complexes as Colon Anticancer Agents

Four new drug-based oxidovanadium (IV) complexes were synthesized and characterized by various spectral techniques, including molar conductance, magnetic measurements, and thermogravimetric analysis. Moreover, optimal structures geometry for all syntheses was obtained by the Gaussian09 program via the DFT/B3LYP method and showed that all of the metal complexes adopted a square-pyramidal structure. The essential parameters, electrophilicity (ω) value and expression for the maximum charge that an electrophile molecule may accept (ΔN_max) showed the practical biological potency of [VO(CTZ)₂] 2H₂O. The complexes were also evaluated for their propensity to bind to DNA through UV–vis absorption titration. The result revealed a high binding ability of the [VO(CTZ)₂] 2H₂O complex with K_b = 1.40 × 10⁶ M⁻¹. Furthermore, molecular docking was carried out to study the behavior of the VO (II) complexes towards colon cancer cell (3IG7) protein. A quantitative structure–activity relationship (QSAR) study was also implemented for the newly synthesized compounds. The results of validation indicate that the generated QSAR model possessed a high predictive power (R² = 0.97). Within the investigated series, the [VO(CTZ)₂] 2H₂O complex showed the greatest potential the most selective compound comparing to the stander chemotherapy drug.     

Synthesis,Antibacterial and Anthelmintic Activity of Novel 3-(3-Pyridyl)-oxazolidinone-5-methyl Ester Derivatives

In this study, a series of 3-(3-pyridyl)-oxazolidone-5-methyl ester derivatives was synthesized and characterized by ¹H NMR, ¹³C NMR, and LC-MS. The conducted screening antibacterial studies of the new 3-(3-pyridyl)-oxazolidone-5-methyl ester derivatives established that the methyl sulfonic acid esters have broad activity spectrum towards Staphylococcus aureus, Streptococcus pneumoniae, Bacillus subtilis and Staphylococcus epidermidis. Among them, compound 12e has the most potent activity, with an MIC of 16 μg/mL against B.subtilis, and could reduce the instantaneous growth rate of bacteria. Furthermore, molecular docking studies were also simulated for compound 12e to predict the specific binding mode of this compound. In addition, anthelmintic activity of these compounds was also evaluated against adult Indian earthworms (Pheretima posthuman). The results showed that compound 11b had the best effect. These results above can provide experimental reference for the development of novel antibacterial and anthelmintic drugs.     

Alpha-Glucosidase Inhibition and Molecular Docking of Isolated Compounds from Traditional Thai Medicinal Plant,Neuropeltis racemosa Wall.

Neuropeltis racemosa Wall. (Convolvulaceae) is wildly distributed in Asia. Its stem is used as the component in traditional Thai recipes for treatments of muscle rigidity, skin disorder, dysentery, and hypoglycemia. However, the chemical constituents and biological activities of N. racemosa have not been reported. From a screening assay, N. racemosa stem crude extract showed the potent effect on alpha-glucosidase inhibition at 2 mg/mL as 96.09%. The bioassay-guiding isolation led to 5 compounds that were identified by spectroscopic techniques as scopoletin (1), syringic acid (2), methyl 3-methyl-2-butenoate (3), N-trans-feruloyltyramine (4), and N-trans- coumaroyltyramine (5). Compounds 1, 4, and 5 exhibited an IC₅₀ of 110.97, 29.87, and 0.92 µg/mL, respectively, while the IC₅₀ of positive standard, acarbose was 272.72 µg/mL. Kinetic study showed that compound 1 performed as the mixed-type inhibition mechanism, whereas compounds 4 and 5 displayed the uncompetitive inhibition mechanism. The docking study provided the molecular understanding of isolated aromatic compounds (1, 2, 4 and 5) to alpha-glucosidase. Hence, this study would be the first report of isolated compounds and their anti-alpha-glucosidase activity with the mechanism of action from N. racemosa. Thus, these active compounds will be further studied to be the lead compounds among natural antidiabetic drugs.     

Synthesis,Biological Evaluation and Molecular Docking Studies of 5-Indolylmethylen-4-oxo-2-thioxothiazolidine Derivatives

Background: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2^® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds. Results: All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6–17-fold) and ketoconazole (13–52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents. Conclusion: Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents.     

Hit-to-Lead Short Peptides against Dengue Type 2 Envelope Protein: Computational and Experimental Investigations

Data from the World Health Organisation show that the global incidence of dengue infection has risen drastically, with an estimated 400 million cases of dengue infection occurring annually. Despite this worrying trend, there is still no therapeutic treatment available. Herein, we investigated short peptide fragments with a varying total number of amino acid residues (peptide fragments) from previously reported dengue virus type 2 (DENV2) peptide-based inhibitors, DN58wt (GDSYIIIGVEPGQLKENWFKKGSSIGQMF), DN58opt (TWWCFYFCRRHHPFWFFYRHN), DS36wt (LITVNPIVTEKDSPVNIEAE), and DS36opt (RHWEQFYFRRRERKFWLFFW), aided by in silico approaches: peptide–protein molecular docking and 100 ns of molecular dynamics (MD) simulation via molecular mechanics using Poisson–Boltzmann surface area (MMPBSA) and molecular mechanics generalised Born surface area (MMGBSA) methods. A library of 11,699 peptide fragments was generated, subjected to in silico calculation, and the candidates with the excellent binding affinity and shown to be stable in the DI-DIII binding pocket of DENV2 envelope (E) protein were determined. Selected peptides were synthesised using conventional Fmoc solid-phase peptide chemistry, purified by RP-HPLC, and characterised using LCMS. In vitro studies followed, to test for the peptides’ toxicity and efficacy in inhibiting the DENV2 growth cycle. Our studies identified the electrostatic interaction (from free energy calculation) to be the driving stabilising force for the E protein–peptide interactions. Five key E protein residues were also identified that had the most interactions with the peptides: (polar) LYS36, ASN37, and ARG350, and (nonpolar) LEU351 and VAL354; these residues might play crucial roles in the effective binding interactions. One of the peptide fragments, DN58opt_8-13 (PFWFFYRH), showed the best inhibitory activity, at about 63% DENV2 plague reduction, compared with no treatment. This correlates well with the in silico studies in which the peptide possessed the lowest binding energy (−9.0 kcal/mol) and was maintained steadily within the binding pocket of DENV2 E protein during the MD simulations. This study demonstrates the use of computational studies to expand research on lead optimisation of antiviral peptides, thus explaining the inhibitory potential of the designed peptides.     

Novel Tyrosine Kinase Inhibitors to Target Chronic Myeloid Leukemia

This paper reports on a novel series of tyrosine kinase inhibitors (TKIs) potentially useful for the treatment of chronic myeloid leukemia (CML). The newly designed and synthesized compounds are structurally related to nilotinib (NIL), a second-generation oral TKI, and to a series of imatinib (IM)-based TKIs, previously reported by our research group, these latter characterized by a hybrid structure between TKIs and heme oxygenase-1 (HO-1) inhibitors. The enzyme HO-1 was selected as an additional target since it is overexpressed in many cases of drug resistance, including CML. The new derivatives 1a–j correctly tackle the chimeric protein BCR-ABL. Therefore, the inhibition of TK was comparable to or higher than NIL and IM for many novel compounds, while most of the new analogs showed only moderate potency against HO-1. Molecular docking studies revealed insights into the binding mode with BCR-ABL and HO-1, providing a structural explanation for the differential activity. Cytotoxicity on K562 CML cells, both NIL-sensitive and -resistant, was evaluated. Notably, some new compounds strongly reduced the viability of K562 sensitive cells.