Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors

Lagorce, David; Douguet, Dominique; Miteva, Maria A.; Villoutreix, Bruno O.

doi:10.1038/srep46277

Cited by 166 publications

(121 citation statements)

References 144 publications

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“…The search for understanding the physicochemical properties of small molecules has greatly increased. The understanding of these properties is necessary in the design of new pharmacological compounds with the ability to bind to various biological targets and present beneficial effects to the body, leading to the discovery of new treatments for diseases of more complex origin, such as Alzheimer’s disease [19] .…”

Section: Discussion / Conclusionmentioning

confidence: 99%

“…It was developed to direct the choice of new drug candidate molecules and was also the pioneer in applying these rules to the drug-likeness profile of a given molecule with its physicochemical properties. According to this rule, for a given molecule to be permeable to cell membranes and also to have easy absorption by means of passive diffusion in the intestinal region, it needs to match the following parameters: LogP≤5; PM≤500; HBA≤ 10 and HBD≤5 [19,23] . And riparin B meets all these requirements, without violation (Log P: 2.77; PM: 285.34; HBA: 4; HBD: 1).…”

Section: Discussion / Conclusionmentioning

confidence: 99%

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In-silico studies of Riparin B in the design of drugs: Physicochemical, pharmacokinetic and pharmacodynamic parameters

Rodrigues¹,

Oliveira²,

Costa

et al. 2020

Preprint

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27The process involved in the research, discovery and development of drugs is 28 characterized by high extensive and complex cost linked to scientific and 29 technological innovations, and it is necessary to study and verify the progress of 30 research carried out in the field that results in patent applications. Aniba riparia 31 (Nees) Mez is a plant species often used for therapeutic purposes, where its 32 pharmacological properties are associated to the presence of alkaloids called 33 riparins. 5 synthetic analog compounds (riparins A, B, C, D, E and F) were 34 developed from natural riparins. These molecules, natural and synthetic, showed 35 several pharmacological activities in tests performed in vitro and in vivo, 36 highlighting the Central Nervous System (CNS). The objective of this work was 37 to evaluate the physical-chemical, pharmacokinetic parameters (absorption, 38 distribution, metabolism, excretion and toxicity) and pharmacodynamic 39 parameters (bioactivity and adverse reactions) of Riparin B by means of in silico 40 computational prediction. Online software such as Pre-ADMET, SwissADME, 41 Molinspiration and PASS on line were used for the analysis. Riparin B fits the 42 characteristics of druglikeness, pharmacokinetic properties appropriate to the 43 predicted patterns and activities within the scope for the treatment of AD, 44 demonstrating a possible potential in the inhibition of AChE. Therefore, in silico 45 results allow us to conclude that riparin B is predicted to be a potential future drug 46 candidate, especially via oral administration, due to its relevant Drug-likeness 47 profile, bioavailability, excellent liposolubility and adequate pharmacokinetics,48including at the level of CNS, penetrating the blood-brain barrier. 49 50 73the natural molecules of this species, there are synthetic analogues known as 74 riparins A, B, C, D and F, which share structures similar to natural molecules [5] . 75 4 Synthetic riparin analogues have already demonstrated antioxidant, 76including analysis of isolated mitochondria of the brain of mice [6,7] , antimicrobial [8] , 77 antiparasitic [9] , as well as leishmanicide [10] , vasodilator [7] and anti-inflammatory [11] 78 activities. Among the properties of synthetic riparins, their action in the Central 79Nervous System (CNS), such anxiolytic effects [12] in anxiety models, without 80 affecting the locomotion of the animals used in the experiment [7] , which make 81 them target molecules of new studies aimed at obtaining therapeutic alternatives, 82 and can be used in the treatment of AD. 83However, there is a significant problem that still remains in the drug 84 discovery procedure, particularly in the later stages of conducting research: the 85 analysis of the properties of ADME (absorption, distribution, metabolism and 86 excretion) and the evident toxicity of drug candidates. Over 50% of drug 87 candidates fail due to poor analysis of ADME/Tox during a drug design [2] . 88 To evaluate the physicochemical, pharmacokinetic (absorption,...

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Section: Discussion / Conclusionmentioning

confidence: 99%

Section: Discussion / Conclusionmentioning

confidence: 99%

In-silico studies of Riparin B in the design of drugs: Physicochemical, pharmacokinetic and pharmacodynamic parameters

Rodrigues¹,

Oliveira²,

Costa

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Physicochemical property is an important attribute of a molecule which influences efficacy, safety or metabolism and can be predicted by using Lipinski's rule of five (RO5); molecular mass < 500; hydrogen-bond donors (HBD) < 5; hydrogen-bond acceptors (HBA) < 10; and LogP < 5 [33]. The rule suggests that molecules, whose properties fell outside some of these boundaries, would be unlikely to become an orally bioavailable drug [34].…”

Section: Physicochemical Evaluation Of Three Molecules With Highest Bmentioning

confidence: 99%

“…The ADMET/pharmacokinetic properties assessments were carried out using combined Simulation Plus ADMET Predictor™ 9.0 [33] and Swiss ADME tool with a proficient method of Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) [38]. The obtained results for ADMET/pharmacokinetic properties presented in Table 7 revealed that all the selected molecules possessed the attribute for central nervous system (CNS) blood-brain barrier (BBB) penetration and with high gastrointestinal (GI) absorption in comparison with their Log BB values.…”

Section: Admet/pharmacokinetic Properties Of the Selected Three Molecmentioning

confidence: 99%

“…Certainly, a random block of cardiac human ether-a-go-go-related gene (hERG) channels by a variety of molecules is a major therapeutic challenge with profound impacts on human health [41]. Hence, molecules with hERG toxicity endpoints (pIC 50 ≥ 6) are likely to exhibit some hERG toxicity [33]. Luckily enough, all the three molecules and including the approved drug (Methylphenidate HCl) have predicted toxicity endpoints (pIC 50 ≥ 6) except for molecule No 12 that has toxicity endpoints (pIC 50 = 6.866).…”

Section: Admet/pharmacokinetic Properties Of the Selected Three Molecmentioning

confidence: 99%

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QSAR modeling, molecular docking and ADMET/pharmacokinetic studies: a chemometrics approach to search for novel inhibitors of norepinephrine transporter as potent antipsychotic drugs

2020

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Chemometrics study that relates biological activity to physicochemical descriptors of a molecule and the prediction of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties in advance are important steps in drugs discovery. In this study, a chemometrics approach was employed on some molecules (inhibitors) of norepinephrine transporter to assess their inhibitory potencies, interactions with the receptor and predict their ADMET/pharmacokinetic properties for identification of novel antipsychotic drugs. The molecules were optimized by using density functional theory at the basis set of B 3 LYP/6-31G*. The genetic function algorithm technique was used to generate a statistically significant model with a good correlation coefficient R 2 Train = 0.952 Cross-validated coefficient Q 2 cv = 0.870, and adjusted squared correlation coefficient R 2 adj = 0.898. The molecular docking simulation using a neurotransmitter transporter receptor (PDB Code 2A65) revealed that three inhibitors (molecule No 38, 44 and 12) exhibited the highest binding affinity of − 10.3, − 9.9 and − 9.3 kcal/mol, respectively, were observed to inhibit the target by forming strong hydrogen bonds with hydrophobic interactions. The physicochemical and ADMET/pharmacokinetic properties result showed that these three molecules are orally bioavailable, high gastrointestinal absorption, good permeability and non-inhibitors of CYP3A4 and CYP2D6 except for molecule No 38. Also, Molecules No 38 and 44 proved to be non-substrate of P-glycoprotein and nontoxicity to a human ether-ago -gorelated gene with predicted hERG toxicity endpoints (pIC 50 < 6) and low ADMET_Risk (< 7.0). The results of this study would provide physicochemical and pharmacokinetics properties needed to identify potent antipsychotic drugs and other relevant information in drug discovery.

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Challenges of peptide and protein drug delivery by oral route: Current strategies to improve the bioavailability

Verma

Goand

Husain

et al. 2021

Drug Development Research

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Advancement in biotechnology provided a notable expansion of peptide and protein therapeutics, used as antigens, vaccines, hormones. It has a prodigious potential to treat a broad spectrum of diseases such as cancer, metabolic disorders, bone disorders, and so forth. Protein and peptide therapeutics are administered parenterally due to their poor bioavailability and stability, restricting their use. Hence, research focuses on the oral delivery of peptides and proteins for the ease of self‐administration. In the present review, we first address the main obstacles in the oral delivery system in addition to approaches used to enhance the stability and bioavailability of peptide/protein. We describe the physiochemical parameters of the peptides and proteins influencing bioavailability in the systemic circulation. It encounters, many barriers affecting its stability, such as poor cellular membrane permeability at the GIT site, enzymatic degradation (various proteases), and first‐pass hepatic metabolism. Then describe the current approaches to overcome the challenges mentioned above by the use of absorption enhancers or carriers, structural modification, formulation and advance technology.

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Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors

Cited by 166 publications

References 144 publications

In-silico studies of Riparin B in the design of drugs: Physicochemical, pharmacokinetic and pharmacodynamic parameters

In-silico studies of Riparin B in the design of drugs: Physicochemical, pharmacokinetic and pharmacodynamic parameters

QSAR modeling, molecular docking and ADMET/pharmacokinetic studies: a chemometrics approach to search for novel inhibitors of norepinephrine transporter as potent antipsychotic drugs

Challenges of peptide and protein drug delivery by oral route: Current strategies to improve the bioavailability

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