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A head-to-head comparison of MM/PBSA and MM/GBSA in predicting binding affinities for the CB1 cannabinoid ligands

Yau MQ, Liew CWY, Toh JH, Loo JSE

J Mol Model, 2024 Oct 31;30(11):390.
PMID: 39480515 DOI: 10.1007/s00894-024-06189-4

CONTEXT: The substantial increase in the number of active and inactive-state CB1 receptor experimental structures has provided opportunities for CB1 drug discovery using various structure-based drug design methods, including the popular end-point methods for predicting binding free energies-Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). In this study, we have therefore evaluated the performance of MM/PBSA and MM/GBSA in calculating binding free energies for CB1 receptor. Additionally, with both MM/PBSA and MM/GBSA being known for their highly individualized performance, we have evaluated the effects of various simulation parameters including the use of energy minimized structures, choice of solute dielectric constant, inclusion of entropy, and the effects of the five GB models. Generally, MM/GBSA provided higher correlations than MM/PBSA (rMM/GBSA = 0.433 - 0.652 vs. rMM/PBSA = 0.100 - 0.486) regardless of the simulation parameters, while also offering faster calculations. Improved correlations were observed with the use of molecular dynamics ensembles compared with energy minimized structures and larger solute dielectric constants. Incorporation of entropic terms led to unfavorable results for both MM/PBSA and MM/GBSA for a majority of the dataset, while the evaluation of the various GB models exerted a varying effect on both the datasets. The findings obtained in this study demonstrate the utility of MM/PBSA and MM/GBSA in predicting binding free energies for the CB1 receptor, hence providing a useful benchmark for their applicability in the endocannabinoid system as well as other G protein-coupled receptors.
METHODS: The study utilized the docked dataset (Induced Fit Docking with Glide XP scoring function) from Loo et al., consisting of 46 ligands-23 agonists and 23 antagonists. The equilibrated structures from Loo et al. were subjected to 30 ns production simulations using GROMACS 2018 at 300 K and 1 atm with the velocity rescaling thermostat and the Parinello-Rahman barostat. AMBER ff99SB*-ILDN was used for the proteins, General Amber Force Field (GAFF) was used for the ligands, and Slipids parameters were used for lipids. MM/PBSA and MM/GBSA binding free energies were then calculated using gmx_MMPBSA. The solute dielectric constant was varied between 1, 2, and 4 to study the effect of different solute dielectric constants on the performance of MM/PB(GB)SA. The effect of entropy on MM/PB(GB)SA binding free energies was evaluated using the interaction entropy module implemented in gmx_MMPBSA. Five GB models, GBHCT, GBOBC1, GBOBC2, GBNeck, and GBNeck2, were evaluated to study the effect of the choice of GB models in the performance of MM/GBSA. Pearson correlation coefficients were used to measure the correlation between experimental and predicted binding free energies.

Matched MeSH terms: Cannabinoids/metabolism; Cannabinoids/pharmacology; Cannabinoids/chemistry
A review on the abuse of three NPS (synthetic cannabinoids, kratom, poppers) among youths in Asia

Bae K, Kwon NJ, Han E

Forensic Sci Int, 2018 Nov;292:45-49.
PMID: 30273913 DOI: 10.1016/j.forsciint.2018.09.008

Abuse of new psychoactive substances (NPSs) among youths is increasing at an unprecedented rate all over the world. In Asia, abuse of synthetic cannabinoids (SCs), kratom, and poppers has been reported, but up to date information related to abuse of these three NPSs is lacking. This literature review focuses on the recent abuse of these three NPS among Asian youth. Many studies have been conducted to investigate the abuse statuses of SCs in Asian youth in Turkey, Japan, and Korea, and many cases of kratom abuse have been reported in Malaysia and Thailand. In addition, concerns have been expressed about the use of kratom in combination with other substances by teenagers. Popper abuse has been reported among many young people in Asia, including Korea and China, and many studies on popper abuse have focused on men who have sex with men in China and Malaysia. Since NPS abuse can have severe adverse effects and create social problems, there is a continuing need to investigate NPS abuse status continuously among young people.

Matched MeSH terms: Cannabinoids/adverse effects
Fulltext A three year study on drug abuse tests at Hospital Tengku Ampuan Rahimah (HTAR), Selangor Malaysia

Lee SP

Malaysian Journal of Social Sciences and Humanities, 2019;4(7):187-196.
MyJurnal

This study focused on drug epidemic in Selangor for 3 consecutive years (2016-2018). Hospital Tengku Ampuan Rahimah (HTAR) analysed an estimate of 12988 samples for drug abuse (opiates and cannabinoids) from 2016 until 2018. Being the centre for receiving samples collected by Police and National Anti-Drug agencies in Southwest Selangor, these areas were combed for analytical study of habitual abusers, their age-related patterns and ethnic origins for better understanding and planning for advocates of control.

Matched MeSH terms: Cannabinoids
Fulltext Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes

di Giacomo V, Chiavaroli A, Recinella L, Orlando G, Cataldi A, Rapino M, et al.

Int J Mol Sci, 2020 05 18;21(10).
PMID: 32443623 DOI: 10.3390/ijms21103575

Cannabidiol (CBD) and cannabigerol (CBG) are Cannabis sativa terpenophenols. Although CBD's effectiveness against neurological diseases has already been demonstrated, nothing is known about CBG. Therefore, a comparison of the effects of these compounds was performed in two experimental models mimicking the oxidative stress and neurotoxicity occurring in neurological diseases. Rat astrocytes were exposed to hydrogen peroxide and cell viability, reactive oxygen species production and apoptosis occurrence were investigated. Cortexes were exposed to K+ 60 mM depolarizing stimulus and serotonin (5-HT) turnover, 3-hydroxykinurenine and kynurenic acid levels were measured. A proteomic analysis and bioinformatics and docking studies were performed. Both compounds exerted antioxidant effects in astrocytes and restored the cortex level of 5-HT depleted by neurotoxic stimuli, whereas sole CBD restored the basal levels of 3-hydroxykinurenine and kynurenic acid. CBG was less effective than CBD in restoring the levels of proteins involved in neurotransmitter exocytosis. Docking analyses predicted the inhibitory effects of these compounds towards the neurokinin B receptor. Conclusion: The results in the in vitro system suggest brain non-neuronal cells as a target in the treatment of oxidative conditions, whereas findings in the ex vivo system and docking analyses imply the potential roles of CBD and CBG as neuroprotective agents.

Matched MeSH terms: Cannabinoids/pharmacology*
The oral administration of Lotus corniculatus L. attenuates acute and chronic pain models in male rats

Jabbari S, Zakaria ZA, Ahmadimoghaddam D, Mohammadi S

J Ethnopharmacol, 2024 Jan 30;319(Pt 1):117181.
PMID: 37734474 DOI: 10.1016/j.jep.2023.117181

ETHNOPHARMACOLOGICAL RELEVANCE: Lotus corniculatus L. (Fabaceae) traditionally used in Persian folk medicine to heal peritoneal inflammation and back pain.
AIM OF THE STUDY: To explore the antinociceptive (acute pain) and anti-neuropathic (chronic pain) activities of Lotus corniculatus leaves essential oil (LCEO) in addition to uncovering the possible mechanisms of antinociception.
MATERIALS AND METHODS: LCEO as well as the pure oleanolic acid (OA) compound, were assayed for their effects on acute (formalin induced paw licking test or FIPT) and chronic (cervical contusion injury models on the fifth cervical vertebra or CCS; 14-day intervals) pain. The possible involvements of NO-cGMP-K+ channel, TRPV, dopamine, cannabinoid, PPAR, adrenergic, and opioid mechanisms in the antinociceptive activity of LCEO have studied by formalin test. The levels of p53 and inflammatory markers were measured using a streptavidin biotin immune peroxidase complex and ELISA methods, respectively.
RESULTS: The LCEO and OA exerted antinociceptive activity in the first-phase of FIPT. Pretreatment with antagonists of TRPV1, dopamine D2, cannabinoid type1 and 2, and NO-cGMP-K+ channel blockers (glibenclamide, L-NAME and methylene blue) attenuated the antinociceptive effect of LCEO in FIPT. In addition, LCEO and OA meaningfully reduced hyperalgesia (days 6-14) and mechanical allodynia (days 2-14) in the CCS model. LCEO suppressed the apoptotic marker (p53) in CCS model and also ameliorated IL-2, TNF-α, and IL-1 in the spinal cord.
CONCLUSION: Finally, LCEO inhibited acute (possibly via the modulation of opioid, TRPV, dopamine, cannabinoid mechanisms as well as NO-cGMP-K+ channel) and chronic pain (via suppressing apoptotic and inflammatory markers) in male rats. The results also suggest that OA has analgesic activity against acute and chronic pain conditions.

Matched MeSH terms: Cannabinoids*
Fulltext Streamlining Natural Products Biomanufacturing With Omics and Machine Learning Driven Microbial Engineering

Ramzi AB, Baharum SN, Bunawan H, Scrutton NS

Front Bioeng Biotechnol, 2020;8:608918.
PMID: 33409270 DOI: 10.3389/fbioe.2020.608918

Increasing demands for the supply of biopharmaceuticals have propelled the advancement of metabolic engineering and synthetic biology strategies for biomanufacturing of bioactive natural products. Using metabolically engineered microbes as the bioproduction hosts, a variety of natural products including terpenes, flavonoids, alkaloids, and cannabinoids have been synthesized through the construction and expression of known and newly found biosynthetic genes primarily from model and non-model plants. The employment of omics technology and machine learning (ML) platforms as high throughput analytical tools has been increasingly leveraged in promoting data-guided optimization of targeted biosynthetic pathways and enhancement of the microbial production capacity, thereby representing a critical debottlenecking approach in improving and streamlining natural products biomanufacturing. To this end, this mini review summarizes recent efforts that utilize omics platforms and ML tools in strain optimization and prototyping and discusses the beneficial uses of omics-enabled discovery of plant biosynthetic genes in the production of complex plant-based natural products by bioengineered microbes.

Matched MeSH terms: Cannabinoids
Fulltext Cannabis as a risk factor for persistent and severe depression: a case report

Khadijah Hasanah, A.A., Aia Harlina, A.R., Nik Ruzyanei, N.J.

Malaysian Journal of Psychiatry, 2014;23(2):73-76.
MyJurnal

Evidence linking cannabis use and depression remains inconsistent. Variations of clinical features were observed in those with history of cannabis use presented with affective symptoms. We report a case of a 19-year-old male college student with a history of heavy cannabis use for at least seven months. A month after stopping cannabis, he presented with severe persistent depressive symptoms. He had no withdrawal symptoms prior to this. He had severe depressive symptoms with melancholic features and progressed to multiple and serious suicidal attempts. While the use of cannabis is implicated in neither the patient’s diagnosis nor management, its use has a significant role in influencing the clinical features and course of the illness. This case suggests that depression can start long after cessation of cannabis use with the history of cannabis remained as a significant risk factor.

Matched MeSH terms: Cannabinoids
Fulltext Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs

Hassan Z, Bosch OG, Singh D, Narayanan S, Kasinather BV, Seifritz E, et al.

Front Psychiatry, 2017;8:152.
PMID: 28868040 DOI: 10.3389/fpsyt.2017.00152

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug's properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine ("Kratom"), synthetic cannabinoids (e.g., "Spice"), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.

Matched MeSH terms: Cannabinoids