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In-Silico Studies of Riparin B in the Design of Drugs: Physicochemical

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In-Silico Studies of Riparin B in the Design of Drugs: Physicochemical bioRxiv preprint doi: https://doi.org/10.1101/2020.04.24.059626; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 1 1 2 3 4 In-silico studies of Riparin B in the design of drugs: Physicochemical, 5 pharmacokinetic and pharmacodynamic parameters 6 7 In-silico studies of Riparin B in the design of drugs 8 9 Aldenora Maria Ximenes Rodrigues1*, Rayla Kelly Magalhães Costa2, 10 Ranyelison Silva Machado1, Stanley Juan Chavez Gutierrez1, Francisco das 11 Chagas Alves Lima2, Aldeídia Pereira de Oliveira1 12 13 14 15 1Departament of Biophysical and Physiology, Federal University of Piaui, 16 Terezina, Piauí, Brazil 17 2Departament of computational chemistry, State University of Piaui, Terezina, 18 Piauí, Brazil 19 20 21 * Corresponding author 22 E-mail: [email protected] (AMXR) 23 24 25 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.24.059626; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 2 26 Abstract 27 28 The process involved in the research, discovery and development of drugs is 29 characterized by high extensive and complex cost linked to scientific and 30 technological innovations, and it is necessary to study and verify the progress of 31 research carried out in the field that results in patent applications. Aniba riparia 32 (Nees) Mez is a plant species often used for therapeutic purposes, where its 33 pharmacological properties are associated to the presence of alkaloids called 34 riparins. 5 synthetic analog compounds (riparins A, B, C, D, E and F) were 35 developed from natural riparins. These molecules, natural and synthetic, showed 36 several pharmacological activities in tests performed in vitro and in vivo, 37 highlighting the Central Nervous System (CNS). The objective of this work was 38 to evaluate the physical-chemical, pharmacokinetic parameters (absorption, 39 distribution, metabolism, excretion and toxicity) and pharmacodynamic 40 parameters (bioactivity and adverse reactions) of Riparin B by means of in silico 41 computational prediction. Online software such as Pre-ADMET, SwissADME, 42 Molinspiration and PASS on line were used for the analysis. Riparin B fits the 43 characteristics of druglikeness, pharmacokinetic properties appropriate to the 44 predicted patterns and activities within the scope for the treatment of AD, 45 demonstrating a possible potential in the inhibition of AChE. Therefore, in silico 46 results allow us to conclude that riparin B is predicted to be a potential future drug 47 candidate, especially via oral administration, due to its relevant Drug-likeness 48 profile, bioavailability, excellent liposolubility and adequate pharmacokinetics, 49 including at the level of CNS, penetrating the blood-brain barrier. 50 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.24.059626; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 3 51 INTRODUCTION 52 53 The process involved in the research, discovery and development of drugs 54 is characterized by high extensive and complex cost linked to scientific and 55 technological innovations, and it is necessary to study and verify the progress of 56 research carried out in the field that results in patent applications[1]. 57 Based on this principle, the pharmaceutical industry applies high 58 investments in bioprospecting research, although it is aware that research on new 59 drugs is a high-risk market. Thus, drug design strategies began to include 60 molecular recognition studies in biological systems, assuming great importance, 61 as they became fundamental bases for the understanding of properties such as 62 potency, affinity and selectivity and structure-activity. And thus, the 63 biotechnological tools associated with medicinal chemistry methods have gained 64 a prominent role in the development of new molecules with biological activity[2]. 65 In order to avoid this failure, a set of ADME/Tox in silico filters was 66 implemented in most pharmaceutical companies, aiming to discard substances, 67 in the discovery phase, that are likely to fail later. This strategy tends to reduce 68 the probability of failure, reducing time and resources used in research. And so, 69 several softwares were developed that perform different analysis of molecules, 70 inferring on the physicochemical, pharmacokinetic and pharmacodynamic 71 parameters in the development stage[3,4]. 72 The species Aniba riparia is commonly used for medicinal purposes due 73 to its pharmacological properties, attributed to alkaloids called riparins. Besides 74 the natural molecules of this species, there are synthetic analogues known as 75 riparins A, B, C, D and F, which share structures similar to natural molecules[5]. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.24.059626; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 4 76 Synthetic riparin analogues have already demonstrated antioxidant, 77 including analysis of isolated mitochondria of the brain of mice[6,7], antimicrobial[8], 78 antiparasitic[9], as well as leishmanicide[10], vasodilator[7] and anti-inflammatory[11] 79 activities. Among the properties of synthetic riparins, their action in the Central 80 Nervous System (CNS), such anxiolytic effects[12] in anxiety models, without 81 affecting the locomotion of the animals used in the experiment[7], which make 82 them target molecules of new studies aimed at obtaining therapeutic alternatives, 83 and can be used in the treatment of AD. 84 However, there is a significant problem that still remains in the drug 85 discovery procedure, particularly in the later stages of conducting research: the 86 analysis of the properties of ADME (absorption, distribution, metabolism and 87 excretion) and the evident toxicity of drug candidates. Over 50% of drug 88 candidates fail due to poor analysis of ADME/Tox during a drug design[2]. 89 To evaluate the physicochemical, pharmacokinetic (absorption, 90 distribution, metabolism, excretion and toxicity) and pharmacodynamic 91 (bioactivity and adverse reactions) parameters of the Riparin B by means of in 92 silico computational prediction. 93 94 MATERIALS AND METHODS 95 96 This is an experimental, quali-quantitative research, aiming at the drug 97 design by in silico analysis. 98 The design of the riparin B molecule was made through the GaussView 99 6.0 software, the structural parameters calculated through the Gaussian 09W 100 program and transformed into MDL Molfiles by Chem3D, for use in the software. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.24.059626; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 5 101 The computational prediction for riparin B was performed through the 102 online software: Pre-ADMET® (https://preadmet.bmdrc.kr/), SwissADME® 103 (https://swissadme.ch), Molinspiration® (https://www.molinspiration).com/), in 104 order to obtain relative results of physicochemical parameters (lipophilicity (logP), 105 molecular weight, polar surface area, number of hydrogen bond donors and 106 acceptors, number of rotary bonds and solubility in water), drug-likeness profile, 107 pharmacokinetic profile (absorption, distribution, metabolism, excretion and 108 toxicity) of the molecule; and PASS on line 109 (http://www.pharmaexpert.ru/passonline/), which allows to predict results 110 regarding the bioactivity profile (pharmacodynamics) and adverse reactions of 111 the molecule. 112 The ADMET profiles of Riparina B were analyzed in comparison with the 113 properties range for 95% of known drugs and the values were calculated by the 114 the referred software server. 115 116 RESULTS 117 118 Fig 1 shows the structural formula of the riparin B. 119 Fig 1. Structural formula of the riparin B 120 Table 1 presents the physicochemical parameters, lipophilicity and 121 solubility of riparin B predicted by Molinspiration, preADMET and SwissADME 122 software. 123 Table 1 - Physicochemical parameters, lipophilicity and solubility of 124 riparin B bioRxiv preprint doi: https://doi.org/10.1101/2020.04.24.059626; this version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 6 Physicochemical properties Formula C17H19NO3 Molecular weight 285,34 g/mol Number of atoms 21 Number of Arom. atoms. 12 Fraction Csp3 0,24 No. of rotating bonds 7 No. H bond Acceptors 3 No. of H bond Donors 1 No. of O+N (HBA) bonds 4 No. of OH + NH (HBD) bonds 1 Refractivity 81,72 TPSA (Topological polar surface 47,56 Ų area) Lipophilicity P / w log (iLOGP) 2,54 P / w log (XLOGP3) 2,68 P / w log (WLOGP) 2,68 P / w log (MLOGP) 2,56 Log P / w (SILICOS-IT) 3,41 Overall average of the 5 2,77 predictions Solubility in water Log S (ESOL) -3,26 Solubility 1,57e-01 mg/mL; 5,52e-04 mol/L Soluble bioRxiv preprint doi: https://doi.org/10.1101/2020.04.24.059626; this version posted April 27, 2020.
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