Comparative Pharmacology of Direct Oral Anticoagulants and Vitamin K Antagonist

2022

BEMS Reports

Background: Valproic acid (VPA) is a small molecule which is the 3 rd most prescribed drug among anticonvulsant therapeutics. Understanding of the pharmacology of VPA targets will help optimally rationalise the therapeutic effects and also minimise the undesired outcomes. Hence this study analysed the human specific targets of VPA and assessed the affinity of VPA to these targets to interpret potential safe therapeutic range for VPA. Materials and Methods: The targets of VPA were identified from the SwissTargetPrediction server and STITCH database and analysed for their affinity with VPA using Autodock vina 1.2.0. The volume of distribution (Vd, L) and the dose of VPA reported in the DrugBank database was used for estimation of the plasma and CSF concentration. The plasma and CSF Concentration Affinity (CA) ratio of VPA against each of the high affinity targets was assessed at variable Vd (0.1 to 0.4 L/kg) to identify the therapeutic safety window of VPA. Results: The plasma/CSF concentration of VPA range from 170 to 7000 µM and 17 to 700 µM respectively. The plasma concentration achieved was within the safety limits (170 to 700 µM) at higher Vd (>10 L), while at lower Vd (<10L), the plasma or CSF concentration achieved was of concern at VPA dose of >1000 mg/day. The plasma concentration at very low Vd (< 2L) was of concern even at dose of 500 mg/day. The affinity of VPA against all its human specific targets ranged from 2.9 to 52.1 mM. The CA ratio of VPA against its high affinity target was observed to be greater than 0.8, indicating potentially significant modulation of these targets. The following four targets showed CA ratio of over 1: PTPRC, KDM5C, GABBR1 and HDAC1, indicating their preferential targeting by VPA. CES1 and SLC22A12 are high affinity targets of VPA which can contribute to its undesired pharmacological effects (CNS oedema and hepatotoxicity). Conclusion: This study offers a novel insight into the anticonvulsant and undesired pharmacology of VPA by specifically identifying the targets involved and recommends an evidence-based approach to personalise dose titration of VPA to achieve optimal therapeutic benefits.

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…proteinatlas.org) and compared. 9,11 For the analysis in this study only high protein expression values was considered while the medium and low expression tissues/organs were ignored.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

PTPRC, KDM5C, GABBR1 and HDAC1 are the Major Targets of Valproic Acid in Regulation of its Anticonvulsant Pharmacological Effects

2022

BEMS Reports

PTPRC, KDM5C, GABBR1 and HDAC1 are the major targets of valproic acid in regulation of its anticonvulsant pharmacological effects

2022

Preprint

Background: Valproic acid (VPA) is a small molecule which is the 3rd most prescribed drug among anticonvulsant therapeutics. Understanding of the pharmacology of VPA targets will help optimally rationalise the therapeutic effects and also minimise the undesired outcomes. Hence this study analysed the human specific targets of VPA and assessed the affinity of VPA to these targets to interpret potential safe therapeutic range for VPA. Materials and Methods: The targets of VPA were identified from the SwissTargetPrediction server and STITCH database and analysed for their affinity with VPA using Autodock vina 1.2.0. The volume of distribution (Vd, L) and the dose of VPA reported in the DrugBank database was used for estimation of the plasma and CSF concentration. The plasma and CSF Concentration Affinity (CA) ratio of VPA against each of the high affinity targets was assessed at variable Vd (0.1 to 0.4 L/kg) to identify the therapeutic safety window of VPA. Results: The plasma/CSF concentration of VPA range from 170 to 7000 microM and 17 to 700 microM respectively. The plasma concentration achieved was within the safety limits (170 to 700 microM) at higher Vd (>10 L), while at lower Vd (<10L), the plasma or CSF concentration achieved was of concern at VPA dose of >1000 mg/day. The plasma concentration at very low Vd (< 2L) was of concern even at dose of 500 mg/day. The affinity of VPA against all its human specific targets ranged from 2.9 to 52.1 mM. The CA ratio of VPA against its high affinity target was observed to be greater than 0.8, indicating potentially significant modulation of these targets. The following four targets showed CA ratio of over 1: PTPRC, KDM5C, GABBR1 and HDAC1, indicating their preferential targeting by VPA. CES1 and SLC22A12 are high affinity targets of VPA which can contribute to its undesired pharmacological effects (CNS oedema and hepatotoxicity). Conclusion: This study offers a novel insight into the anticonvulsant and undesired pharmacology of VPA by specifically identifying the targets involved and recommends an evidence based approach to personalise dose titration of VPA to achieve optimal therapeutic benefits.

Analysing the role of SERPINE1 network in the pathogenesis of human glioblastoma

Kaliaperumal

Khosravi

2022

Preprint

Background: Glioblastoma multiforme (GBM) is one of the most aggressive and difficult to treat brain tumour in humans with a 5 year survival rate of less than 6%. SERPINE1 is a novel tumour receptor found on GBM that modulates the progression of this cancer through growth signals and remodelling of the extracellular matrix. Hence, we investigated the role of SERPINE1 and its network proteins in pathogenesis of GBM and assessed its targetability. Material and methods: Network proteins of SERPINE1 in homo sapiens was identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software. The expression profile of SERPINE1 in the different brain regions was evaluated to correlate its relevance to GBM pathology. Selected small molecules from Calotropis gigantea were screened using AutoDock vina to assess targetability of human SERPINE1. Results: VTN, PLG, TGFB1, VWF, FGF2 and CXCR1 were identified as the major network proteins of SERPINE1. The strongest interaction was observed between SERPINE1 and FGF2 (42884 H-bonds) followed by CXCR1 (20279 H-bonds). Our results suggest that SERPINE1 and its network proteins identified here play a vital role in GBM development and progression through brain parenchyma by creating the prime microenvironment for carcinogenesis, tumour invasion and migration. The highest expression of SERPINE1 was observed in the pons, medulla, midbrain, corpus callosum and spinal cord. Expression of SERPINE1 was consistent with high grade lesions of GBM, suggesting association of SERPINE1 with advanced stages of GBM. The selected small molecules from Calotropis gigantea were observed to have therapeutically feasible binding affinity (140 - 550 microM) and predicted efficacy (290 - 1115 microM) against human SERPINE1. Conclusion: SERPINE1 plays a vital role in the progression of GBM through its critical network proteins identified in this study. The expression of SERPINE1 aligns with the advanced stages of GBM. Small molecules from Calotropis gigantea tested in this study can serve as lead compounds for developing novel anti- SERPINE1 therapeutics for advanced stages of GBM.