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

Photo-and thermoresponsive N-salicylideneaniline derivatives : solid-state studies and structural aspects

Electronic supplementary information (ESI) available. CCDC 1899401, 1902658, 1966932, 1989369, 1989398, 1989403, 2014911, 2014914, 2019418, 2049690, 2049691, 2062423, 2157376, 2156456–2156467 and 2191107–2191119. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi. org/10.1039/d1nj03056f.N-Salicylideneaniline (SA) and its derivatives are known to possess chromism upon exposure to external stimuli. Herein, we present mechanochemical synthesis of a series of photo-and thermoresponsive SA-derivatives and report on solid-state stabilisation of their tautomeric forms either by change in temperature or by photoirradiation. The influence of UV light on proton transfer between the enol-imine (EI) and keto-amine (KA) forms was investigated at λ1 = 254 and λ2 = 365 nm. Differential scanning calorimetry (DSC) measurements provided extra information on the thermodynamic relationship between the prototropic tautomers, and their exposition to liquid nitrogen, combined with variable temperature single-crystal X-ray diffraction (VT-SCXRD) and spectroscopic data, ascertained structural reasons for the intrinsic thermo-optical properties of the compounds. A series of structural determinations between 150 and 300 K further shed light on the thermomechanical behaviour exhibited by the thermoresponsive compounds. By virtue of calorimetry we were able to demonstrate proton transfer via the intramolecular O⋯N hydrogen bond over the temperature range 193–453 K. This present work demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the switching behaviour between the EI and KA forms. Furthermore, the assertion that it is predominantly the planarity (φ < 25°) that determines thermochromaticity is questioned.The National Research Foundation (NRF), South Africa and Rhodes University Research Council.http://rsc.li/njchj2023Chemistr