Background: Antipsychotics interfere with virtually all hallmarks of cancer, including angiogenesis. Vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth receptors (PDGFRs) play crucial roles in angiogenesis and represent targets of many anti-cancer agents. We assessed and compared the binding effects of antipsychotics and receptor tyrosine kinase inhibitors (RTKIs) on VEGFR2 and PDGFRα. Methods: FDA-approved antipsychotics and RTKIs were retrieved from DrugBank. VEGFR2 and PDGFRα structures were obtained from Protein Data Bank and loaded on Biovia Discovery Studio software to remove nonstandard molecules. Molecular docking was carried out using PyRx and CBDock to determine the binding affinities of protein-ligand complexes. Results: Risperidone exerted the highest binding effect on PDGFRα (-11.0 Kcal/mol) as compared to other antipsychotic drugs and RTKIs. Risperidone also demonstrated a stronger binding effect on VEGFR2 (-9.6 Kcal/mol) than the RTKIs, pazopanib (-8.7 Kcal/mol), axitinib (-9.3 Kcal/mol), vandetanib (-8.3 Kcal/mol), lenvatinib ( -7.6 Kcal/mol) and sunitinib (-8.3 Kcal/mol). Sorafenib (an RTKI), however, exhibited the highest VEGFR2 binding affinity of -11.7 Kcal/mol. Conclusion: Risperidone's superior binding affinity with PDGFRα when compared to all reference RTKIs and antipsychotic drugs, as well as its stronger binding effect on VEGFR2 over the RTKIs, sunitinib, pazopanib, axitinib, vandetanib, and lenvatinib, imply that it could be repurposed to inhibit angiogenic pathways and subjected to pre-clinical and clinical trials for cancer therapy.

Triple-negative breast cancer (TNBC) overexpresses poly-ADP ribose-polymerase (PARP), and histone deacetylase (HDAC) specific isoforms, PARP2 and HDAC7 respectively. There is a paucity of research assessing plant-based alkaloids for the development of HDAC7- and PARP2-isoform specific inhibitor compounds. This study evaluated the pharmacokinetic properties and inhibitory potentials of plant-derived alkaloids, including chelidonine and oxymatrine on PARP2 and HDAC7 using in silico protocols. ADME/T analysis revealed that chelidonine and oxymatrine had high human intestinal absorption and blood-brain barrier permeability, low CYP promiscuity, and no Ames mutagenicity or carcinogenicity. Moreso, chelidonine and oxymatrine had zero violations of the Lipinski rule of five. Chelidonine displayed the greatest PARP2 binding affinity (-9.6 Kcal/mol), when compared to oxymatrine (-8.4 Kcal/mol), co-crystalized ligand (-7.9 Kcal/mol) and the reference veliparib drug (-8.8 Kcal/mol). However, the co-crystalized HDAC-IN-5 had the most favorable binding interaction with HDAC7 (-9.8 Kcal/mol). The binding impact of chelidonine on HDAC7 (-8.6 Kcal/mol) was also greater than that of oxymatrine (-7.3 Kcal/mol) and romidepsin (-7.7 Kcal/mol). Chelidonine exhibited propitious drug-like properties and stronger inhibitory effects on PARP2 and HDAC7 than the reference drugs. This indicates its suitability for progression into pre-clinical and clinical trials for the development of PARP2- and HDAC7-isoform specific inhibitors that could be used for targeted TNBC treatment.

Background: Diabetes mellitus (DM) is a metabolic disorder known to impair many physiological functions via reactive oxygen species (ROS). Aldose reductase, sorbitol dehydrogenase, dipeptidyl peptidase IV, α-amylase and α-glucosidase are pharmacotherapeutic protein targets in type-2 diabetes mellitus (T2DM). Inhibitors of these enzymes constitute a new class of drugs used in the management and treatment of T2DM. Some reports have claimed that medicinal plant extracts that serves as food (and as an antioxidant source) can reduce these alterations by eliminating ROS caused by DM. Ethnobotanical survey claims Jatropha gossypifolia commonly called “fignut” and “Lapa-lapa” in the Yoruba land of South-western Nigeria, to be used for the treatment and management of diabetes, in addition to its nutritive value. Objective: The nutritional composition and in-silico antidiabetic potential of the bioactive constituents of J. gossypifolia leaf extracts were investigated. Methods: Proximate, minerals and gas chromatography–mass spectroscopy (GC-MS) analysis were carried out using standard procedures. Phytocompounds present in J. gossypifolia methanol (JGM) and ethyl acetate (JGE) leaf extracts were tested as potential antagonists of selected protein targets via in-silico techniques. Drug-likeness, pharmacokinetic properties and toxicity of the promising docked ligands were also predicted. Results: The proximate and mineral analysis revealed good nutritional composition and mineral content. Additionally, cyclo-pentadecane and dibutyl phthalate from methanol extract, and benzene- 1,2,4,5-tetramethyl, benzene-1,2,3,5-tetramethyl, and benzene-1,3-dimethyl-5-(1-methylethyl) from ethyl acetate extract were present in J. gossypifolia leaf which exhibited a better binding affinity than the clinically prescribed standard, metformin. Conclusion: Benzene-1,2,4,5-tetramethyl from JGE extracts exhibited the most promising antidiabetic potential in-silico, suggesting its candidature as diabetes-target-protein inhibitor which may be developed for the treatment of type-2 diabetes mellitus.

A computational assessment of alkaloids targeting the plant homeodomain in pygopus2: inhibitory potential and drug-like properties

Datura stramonium, Moringa oleifera and Carica papaya are common plants in Nigeria that have been reported to possess some psychoactive effects. However, the interactions of their alkaloids with the molecular targets of common psychoactive compounds are not well established. This study assessed the interactive potentials of alkaloids from these plants with α4β2 nicotinic acetylcholine receptor (α4β2 nAChR) of nicotine from Nicotiana tabacum and the cannabinoid receptor 1 (CB1) of delta-9-tetrahydrocannabinol (THC) from Cannabis sativa. Protein structures were retrieved from Protein Data Bank while PubChem was used to obtain ligand structures. Molecular docking using UCSF Chimera determined the binding affinity of protein-ligand complexes, followed by molecular dynamics simulations to evaluate root mean square deviation and radius of gyration. ADMET analysis was performed using SwissADME and ProTox-II. Notably, apoatropine, hyoscyamine, and 3â,6â-ditigloyloxytropane from D. stramonium exhibited stronger α4β2 nAChR binding effects, compared to nicotine, and had CB1 binding affinities similar to THC. Among these high-affinity binding compounds, apoatropine maintained the most stable and compact structural conformation, relative to nicotine and THC. ADMET analysis indicated propitious physicochemical and drug-like properties for all plant-based alkaloids except N, α-L-rhamnopyranosyl vincosamide from M. oleifera and apoatropine, which were predicted to be carcinogenic. Additionally, over 50% of the plant-based alkaloids assessed are blood-brain barrier permeant, implying their propensity to mediate CNS effects. It is pertinent to regulate the use of these plants, particularly in tropical regions like Nigeria, where they are widely cultivated, consumed, and likely explored for recreational purposes based on their psychoactive effects.