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Molecules (Basel, Switzerland) Dec 2021This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CL) through molecular docking,...
Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment.
This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CL) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics-generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CL of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from -4.6 ± 0.14 to -7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CL. The free energy of binding also demonstrates the stability of the PP-3CL complexes. Citicoline and uridine triacetate showed free binding energies of -25.53 and -7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.
Topics: Acetates; Antiviral Agents; Coronavirus 3C Proteases; Coronavirus Papain-Like Proteases; Cytidine Diphosphate Choline; Drug Evaluation, Preclinical; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Protease Inhibitors; SARS-CoV-2; Uridine; COVID-19 Drug Treatment
PubMed: 34946540
DOI: 10.3390/molecules26247458 -
British Medical Journal Jun 1963
Topics: Carcinoma, Bronchogenic; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neoplasms; Nitrogen Mustard Compounds; Peptide Nucleic Acids; Polycythemia Vera; Sarcoma; Uracil Mustard
PubMed: 14000759
DOI: 10.1136/bmj.1.5345.1563 -
Blood Mar 1970
Topics: Blood Cell Count; Blood Platelets; Bone Marrow Examination; Busulfan; Coronary Disease; Electrocardiography; Ergotamine; Leukemia, Myeloid; Megakaryocytes; Migraine Disorders; Phosphorus Isotopes; Polycythemia Vera; Thrombocytosis; Uracil Mustard
PubMed: 5265825
DOI: No ID Found -
Molecules (Basel, Switzerland) Oct 2023Natural products are a main source of new chemical entities for use in drug and pesticide discovery. In order to discover lead compounds with high herbicidal activity, a...
Natural products are a main source of new chemical entities for use in drug and pesticide discovery. In order to discover lead compounds with high herbicidal activity, a series of new pyrido[2,3-] pyrimidine derivatives were designed and synthesized using 2-chloronicotinic acid as the starting material. Their structures were characterized with H NMR, C NMR and HRMS, and the herbicidal activities against dicotyledonous lettuce (), field mustard (), monocotyledonous bentgrass () and wheat () were determined. The results indicated that most of the pyrido[2,3-] pyrimidine derivatives had no marked inhibitory effect on lettuce at 1 mM. However, most of the pyrido[2,3-] pyrimidine derivatives possessed good activity against bentgrass at 1 mM. Among them, the most active compound, 3-methyl-1-(2,3,4-trifluorophenyl)pyrido[2,3-]pyrimidine-2,4(1,3)-dione (), was as active as the positive controls, the commercial herbicides clomazone and flumioxazin. Molecular simulation was performed with molecular docking and DFT calculations. The docking studies provided strong evidence that acts as an herbicide by inhibition of protoporphyrinogen oxidase. However, the physiological results indicate that it does not act on this target in vivo, implying that it could be metabolically converted to a compound with a different molecular target.
Topics: Herbicides; Molecular Docking Simulation; Pyrimidines; Brassica; Protoporphyrinogen Oxidase; Structure-Activity Relationship
PubMed: 37959782
DOI: 10.3390/molecules28217363 -
DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards is preserved in intact cells.Nucleic Acids Research Jun 1992Nitrogen mustard alkylating agents react with isolated DNA in a sequence selective manner, and the substituent attached to the drug reactive group can impose a distinct...
Nitrogen mustard alkylating agents react with isolated DNA in a sequence selective manner, and the substituent attached to the drug reactive group can impose a distinct sequence preference. It is not clear however to what extent the observed DNA sequence preferences are preserved in intact cells. The highly reiterated sequence of human alpha DNA has been used to determine the sites of guanine-N7 alkylation following treatment of cells with three nitrogen mustards, mechlorethamine, uracil mustard and quinacrine mustard, known to react in isolated DNA with distinctly different sequence preferences. Alpha DNA from drug treated cells was extracted, purified, end-labeled, and a 296 base pair, singly end-labelled, fragment isolated. Following the quantitative conversion of alkylation sites to strand breaks the fragments were separated on DNA sequencing gels. Clear differences were observed between the alkylation patterns of the three compounds, and the selectivities were qualitatively similar to those predicted and observed in the same sequence alkylated in vitro. In particular the unique preferences of uracil and quinacrine mustards for 5'-PyGC-3' and 5'-GT/GPu-3' sequences, respectively, were preserved in intact cells suggesting that the pattern of sequence dependent reactivity is not grossly affected by the nuclear milieu.
Topics: Alkylation; Base Sequence; DNA; Guanine; Humans; Mechlorethamine; Molecular Sequence Data; Quinacrine Mustard; Tumor Cells, Cultured; Uracil Mustard
PubMed: 1620613
DOI: 10.1093/nar/20.12.3175 -
Nucleic Acids Research Mar 1991The antiviral distamycin A and its phenyl mustard derivative FCE24517 possessing antitumor activity were tested for their ability to inhibit macromolecular synthesis in...
The antiviral distamycin A and its phenyl mustard derivative FCE24517 possessing antitumor activity were tested for their ability to inhibit macromolecular synthesis in three human and one murine cell line. While distamycin A was poorly active in these systems, FCE24517 inhibited DNA synthesis efficiently, RNA synthesis to a lower extent and had little effect on protein synthesis. These findings suggest that the in vivo activity of FCE24517 derives from the specific inhibition of DNA synthesis. When the two drugs were tested on several enzymes involved in human DNA metabolism a strikingly similar pattern of inhibition appeared, with distamycin A being the more potent. Both drugs showed: A), no inhibitory activity against thymidine kinase and DNA primase; B), low activity against DNA topoisomerases I and II and the 3'-5' exonuclease associated with the DNA polymerase epsilon; C), high activity against DNA polymerases alpha and epsilon, uracil-DNA glycosylase and the joining activity of the replicative DNA ligase; D), the highest inhibitory activity against the AMP-dependent DNA relaxing activity of DNA ligase. The strong in vitro inhibition of several DNA enzymatic activities, including DNA ligase, do not match with the in vivo activities of the two drugs. However a unique difference was observed: only FCE24517 inhibited the DNA-independent reaction of adenylation of human DNA ligase while the adenylation reaction of T4 and E. coli DNA ligase was unaffected by either drug. It is still unclear whether these properties are relevant for modulating the killing activity of FCE24517 against proliferating cells both in culture and in vivo. Nevertheless FCE24517 is the first known molecule capable of interacting directly and specifically with human DNA ligase.
Topics: Adenosine Monophosphate; Animals; Antineoplastic Agents; DNA Ligases; DNA Replication; Distamycins; HeLa Cells; Humans; Kinetics; Mice; Nitrogen Mustard Compounds; Protein Biosynthesis; RNA; Tumor Cells, Cultured
PubMed: 1708493
DOI: 10.1093/nar/19.5.1067 -
Nucleic Acids Research Apr 1986Nitrogen mustards alkylate DNA primarily at the N7 position of guanine. Using an approach analogous to that of the Maxam-Gilbert procedure for DNA sequence analysis, we...
Nitrogen mustards alkylate DNA primarily at the N7 position of guanine. Using an approach analogous to that of the Maxam-Gilbert procedure for DNA sequence analysis, we have examined the relative frequencies of alkylation for a number of nitrogen mustards at different guanine-N7 sites on a DNA fragment of known sequence. Most nitrogen mustards were found to have similar patterns of alkylation, with the sites of greatest alkylation being runs of contiguous guanines, and relatively weak alkylation at isolated guanines. Uracil mustard and quinacrine mustard, however, were found to have uniquely enhanced reaction with at least some 5'-PyGCC-3' and 5'-GT-3' sequences, respectively. In addition, quinacrine mustard showed a greater reaction at runs of contiguous guanines than did other nitrogen mustards, whereas uracil mustard showed little preference for these sequences. A comparison of the sequence-dependent variations of molecular electrostatic potential at the N7-position of guanine with the sequence dependent variations of alkylation intensity for mechlorethamine and L-phenylalanine mustard showed a good correlation in some regions of the DNA, but not others. It is concluded that electrostatic interactions may contribute strongly to the reaction rates of cationic compounds such as the reactive aziridinium species of nitrogen mustards, but that other sequence selectivities can be introduced in different nitrogen mustard derivatives.
Topics: Alkylation; Base Sequence; DNA, Viral; Densitometry; Formates; Guanine; Mechlorethamine; Melphalan; Nitrogen Mustard Compounds; Quinacrine Mustard; Structure-Activity Relationship; Substrate Specificity; Sulfuric Acid Esters; T-Phages; Uracil Mustard
PubMed: 3960738
DOI: 10.1093/nar/14.7.2971 -
Proceedings of the National Academy of... Dec 1964
Topics: Animals; Antineoplastic Agents; Carbon Isotopes; Cell Death; DNA; Injections, Intraperitoneal; Macromolecular Substances; Metabolism; Mice; Neoplasm Proteins; Nitrogen Mustard Compounds; Peritoneal Cavity; Pharmacology; Proteins; RNA; Radiometry; Research; Sarcoma 180; Thioguanine; Tritium; Uracil Mustard
PubMed: 14243513
DOI: 10.1073/pnas.52.6.1396 -
Antimicrobial Agents and Chemotherapy Mar 1975The lethality for BALB/c mice of 1,3-bis(2-chloroethyl)-1-nitrosourea, cytosine arabinoside, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, hydroxyurea, mithramycin, a...
The lethality for BALB/c mice of 1,3-bis(2-chloroethyl)-1-nitrosourea, cytosine arabinoside, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, hydroxyurea, mithramycin, a polymyxin-like antibiotic (SQ 21,286), polyadenylic polyuridylic acid, procarbazine, 5-[3,3-bis(2-chloroethyl)-1-triazeno]-imidazole-4-carboxamide (TIC-mustard) or uracil arabinoside administered in combination with Escherichia coli lipopolysaccharide (LPS) was measured. Simultaneously administered mithramycin and LPS or TIC-mustard administered 24 h after LPS synergistically killed mice. Concanavalin A potentiated the lethality of TIC-mustard but not of eight other drugs tested. Pretreatment of mice with LPS or lipid A complexed to concanavalin A rendered mice resistant to the lethal action of LPS alone or combinations of LPS and mithramycin. Mithramycin-treated mice were killed by minute amounts of LPS. Mice sensitized to LPS by mithramycin were used to detect endotoxic activity in biological materials, such as commercially available enzymes, and in a complex of lipid A with concanavalin A.
Topics: Animals; Drug Synergism; Escherichia coli; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Plicamycin
PubMed: 124549
DOI: 10.1128/AAC.7.3.322 -
Journal of Bacteriology Dec 1968The actions of three immunosuppressive drugs on normal antibody synthesis in the adult mouse were determined. Inbred mice were given daily intraperitoneal injections of...
The actions of three immunosuppressive drugs on normal antibody synthesis in the adult mouse were determined. Inbred mice were given daily intraperitoneal injections of actinomycin D, uracil mustard, or cyclophosphamide for extended periods. The sera of treated and untreated mice were assayed for phage-neutralizing activity to monitor the effect of each drug on the amount of circulating normal antibody. Except for an initial decrease in titer of normal anti-phage MSP2 activity, actinomycin D had no significant effect on normal antibody activity. Uracil mustard caused alternating elevation and depression of normal antibody titers. Cyclophosphamide caused a prolonged depression of normal antibody. The response patterns to the three immunosuppressive agents were the same for both induced and normal antibody.
Topics: Animals; Antibodies; Antibody Formation; Bacteriophages; Cyclophosphamide; Dactinomycin; Immunosuppressive Agents; Mice; Neutralization Tests; Uracil Mustard
PubMed: 5724964
DOI: 10.1128/jb.96.6.1931-1934.1968