39 research outputs found
Structure based docking and molecular dynamic studies of plasmodial cysteine proteases against a South African natural compound and its analogs:
Identification of potential drug targets as well as development of novel antimalarial chemotherapies with unique mode of actions due to drug resistance by Plasmodium parasites are inevitable. Falcipains (falcipain-2 and falcipain-3) of Plasmodium falciparum, which catalyse the haemoglobin degradation process, are validated drug targets. Previous attempts to develop peptide based drugs against these enzymes have been futile due to the poor pharmacological profiles and susceptibility to degradation by host enzymes. This study aimed to identify potential non-peptide inhibitors against falcipains and their homologs from other Plasmodium species
Characterization of nickel tetrahydroxy phthalocyanine complexes and the electrocatalytic oxidation of 4-chlorophenol
This work reports on the use of nickel(II) tetrahydroxy (NiPc(OH)4) and (poly-Ni(OH)Pc(OH)4) phthalocyanine complexes as films on ordinary poly graphite electrode (OPGE) for the electrochemical oxidation of 4-chlorophenol (4-CP). The NiPc(OH)4 film was electrotransformed to Ni(OH)Pc(OH)4 film in aqueous 0.1 M NaOH solution to the ‘O–Ni–O oxo’ bridge form. The result showed that the Ni(OH)Pc(OH)4 film on OPGE was more electroactive in terms of increase in current and less catalytic in terms of potential compared to the adsorbed NiPc(OH)4 on OPGE. The reactivity of the two molecules was explained by theoretical calculations. The energies of the frontier orbitals of NiPc(OH)4, Ni(OH)Pc(OH)4 and 4-chlorophenol were calculated using density functional theory (DFT) method. The inter molecular hardness (η) and donor–acceptor hardness (ηDA) of Ni(OH)Pc(OH)4, NiPc(OH)4, Ni(OH)Pc(OH)4/4-chlorophenol and NiPc(OH)4/4-chlorophenol were estimated. The Ni(OH)Pc(OH)4, showed stronger interaction with 4-chlorophenol than NiPc(OH)4. DFT method was also used to model IR and Raman spectrum of H2Pc(OH)4 and NiPc(OH)4
SANCDB: a South African natural compound database
Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa
Analysis of non-peptidic compounds as potential malarial inhibitors against Plasmodial cysteine proteases via integrated virtual screening workflow
Falcipain-2 (FP-2) and falcipain-3 (FP-3), haemoglobin-degrading enzymes in Plasmodium
falciparum, are validated drug targets for the development of effective inhibitors against
malaria. However, no commercial drug-targeting falcipains has been developed despite
their central role in the life cycle of the parasites. In this work, in silico approaches are used
to identify key structural elements that control the binding and selectivity of a diverse set of
non-peptidic compounds onto FP-2, FP-3 and homologues from other Plasmodium species
as well as human cathepsins. Hotspot residues and the underlying non-covalent
interactions, important for the binding of ligands, are identified by interaction fingerprint
analysis between the proteases and 2-cyanopyridine derivatives (best hits). It is observed
that the size and chemical type of substituent groups within 2-cyanopyridine derivatives
determine the strength of protein–ligand interactions. This research presents novel results
that can further be exploited in the structure-based molecular-guided design of more
potent antimalarial drugs.http://www.tandfonline.com/loi/tbsd20hb2017Forestry and Agricultural Biotechnology Institute (FABI)Genetic
Analysis of non-peptidic compounds as potential malarial inhibitors against plasmodial cysteine proteases via integrated virtual screening workflow
Malaria is an infectious disease caused by a diverse group of erythrocytic protozoan parasites of the genus Plasmodium. It remains an exigent public health problem in the tropical areas of Africa, South America and parts of Asia and continues to take its toll in morbidity and mortality with half of the world’s population under a permanent risk of infection leading to more than half a million deaths annually (WHO, 2013). Five Plasmodium species, namely P. falciparum (Pf ), P. vivax (Pv), P. ovale (Po), P. malariae (Pm) and P. knowlesi (Pk), are known to infect humans with Pf responsible for more than 90% of the malarial fatalities reported in sub-Saharan Africa. The predominance of Pf is attributed to its adaptability (Ashley, McGready, Proux, & Nosten, 2006; Prugnolle et al., 2011). Although the high occurrence of the Duffy negative trait among African populations lowers the threat posed by Pv, it is the most frequent and widely causative agent of benign tertian malaria in other parts of the world (Mendis, Sina, Marchesini, & Carter, 2001). In addition to the listed human malarial parasite forms, several other Plasmodium species, which infect non-human laboratory models, have been identified and are of significant importance in understanding the parasite biology, the host–parasite interactions and in the drug development process (Langhorne et al., 2011)
Structure based docking and molecular dynamic studies of plasmodial cysteine proteases against a South African natural compound and its analogs
Identification of potential drug targets as well as development of novel antimalarial chemotherapies
with unique mode of actions due to drug resistance by Plasmodium parasites are inevitable. Falcipains
(falcipain-2 and falcipain-3) of Plasmodium falciparum, which catalyse the haemoglobin degradation
process, are validated drug targets. Previous attempts to develop peptide based drugs against these
enzymes have been futile due to the poor pharmacological profiles and susceptibility to degradation
by host enzymes. This study aimed to identify potential non-peptide inhibitors against falcipains and
their homologs from other Plasmodium species. Structure based virtual docking approach was used
to screen a small non-peptidic library of natural compounds from South Africa against 11 proteins. A
potential hit, 5α-Pregna-1,20-dien-3-one (5PGA), with inhibitory activity against plasmodial proteases
and selectivity on human cathepsins was identified. A 3D similarity search on the ZINC database using
5PGA identified five potential hits based on their docking energies. The key interacting residues of
proteins with compounds were identified via molecular dynamics and free binding energy calculations.
Overall, this study provides a basis for further chemical design for more effective derivatives of these
compounds. Interestingly, as these compounds have cholesterol-like nuclei, they and their derivatives
might be well tolerated in humans.The
National Institutes of Health Common Fund under grant number U41HG006941 to H3ABioNet; the National
Research Foundation (NRF), South Africa [grant numbers 79765].http://www.nature.com/srepam2016Forestry and Agricultural Biotechnology Institute (FABI)Genetic
Erosión por labranza con arado de disco en suelos volcánicos de ladera en Costa Rica
Este trabajo midió el movimiento de suelo por labranza y erosión al utilizar el arado de disco, el implemento de labranza primaria más común en la región cultivada en las faldas del volcán Irazú. Los resultados revelaron que el potencial de erosión por labranza es muy alto, tanto así que los valores de erosividad de la labranza por el arado de disco fueron el doble de los reportados en implementos de labranza primaria utilizados en Europa y Norte América. Se concluyó que la reducción de erosión del suelo por labranza y agua es necesaria para mantener una producción agrícola viable a largo plazo en esta región de Costa Rica
Theoretical and photodynamic therapy characteristics of heteroatom doped detonation nanodiamonds linked to asymmetrical phthalocyanine for eradication of breast cancer cells
An amide mono substituted benzothiozole phthalocyanine: zinc(II) 3-(4-((3,17,23-tris(4-(benzo [d]thiazol-2-yl)phenoxy)-9-yl)oxy) phenyl)amide phthalocyanine (NH2BzPc) was covalently linked to undoped and heteroatom doped detonation nanodiamonds (DNDs): B@DNDs, P@DNDs, S@DNDs, N@DNDs, and SandN@DNDs There is a drastic decrease in highest occupied molecular orbital (HOMO) – lowest unoccupied molecular orbital (LUMO) energy gaps for nanoconjugates compared to DNDs alone. B@DNDs-NH2BzPc, SandN@DNDs-NH2BzPc, and P@DNDs-NH2BzPc showed superior photodynamic therapy (PDT) effects. DNDs-NH2BzPc also had a small HOMO-LUMO gap, but did not show improved PDT activity compared to the Pc alone, suggesting doping of DNDs is important. This study shows improved PDT effect on Michigan Cancer Foundation-7 breast cancer lines at 7.63%, 7.62% and 6.5% cell viability for P@DNDs-NH2BzPc, SandN@DNDs-NH2BzPc and B@DNDs-NH2BzPc, respectively
Potential repurposing of four FDA approved compounds with antiplasmodial activity identified through proteome scale computational drug discovery and in vitro assay
Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36×796) dockings
Synthesis of N-Substituted phosphoramidic acid esters as “reverse” fosmidomycin analogues
An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”