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Molecular Docking Studies of Some Novel Fluoroquinolone Derivatives

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Molecular Docking Studies of Some Novel Fluoroquinolone Derivatives Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 30 January 2019 doi:10.20944/preprints201901.0307.v1 1 Article 2 Molecular Docking Studies of Some Novel 3 Fluoroquinolone Derivatives 4 Lucia Pintilie* and Amalia Stefaniu 5 1 National Institute for Chemical‐Pharmaceutical Research and Development, 112 Vitan Av., 74373, 6 Bucharest, Romania, e‐mails: [email protected] (L.P), [email protected] (A.S) 7 * Correspondence: [email protected]; Tel.: +40 21 322 29 17 8 9 10 Abstract: An important parameter in the development of a new drug is the drugʹs affinity to the 11 identified target (protein/enzyme). Predicting the ligand binding to the protein assembly by 12 molecular simulations would allow the synthesis to be restricted to the most promising drug 13 candidates. A restricted hybrid HF‐DFT calculation was performed in order to obtain the most stable 14 conformer of studied ligands and a series of DFT calculations using the B3LYP levels with 6‐31G* 15 basis set has been conducted on their optimized structures. The docking studies of the quinolone 16 compounds have been carried out with CLC Drug Discovery Workbench software to identify and 17 visualize the ligand‐receptor interaction mode. 18 Keywords: molecular docking; fluoroquinolones; antimicrobial activity 19 20 1. Introduction 21 Infectious diseases are the second important cause of death global [1]. Treatment of infectious 22 diseases becomes more difficult when common pathogens, such as Staphylococcus aureus and 23 Mycobacterium tuberculosis develop drug resistance to drugs that were considered at one time, 24 effective. Antibiotic drugs are a special class of therapeutic agents whose misuse have affected not 25 only the individual patient, they have affected also the entire community. This is why, at some point 26 after the widespread introduction and use of new antibiotics, antibiotic‐resistant bacteria occurring 27 in significant waves appear almost inevitable. In medical practice, many fluoroquinolones with 28 antimicrobial activity are used, some of them are considered by pharmacists as the primary drugs in 29 anti‐infective therapy. Fluoroquinolones have a broad spectrum and a strong antibacterial activity [2‐ 30 8]. They are characterized by pharmacokinetics that allows their use in all localized infections. In the 31 development of a new antimicrobial agent, an important parameter is the affinity of a drug to the 32 identified target (protein/enzyme). Predicting the binding of the ligand with the target 33 (protein/enzyme) by molecular simulation would allow to restrict the synthesis to the most promising 34 compounds [9‐20]. Molecular docking can be accomplished by two interdependent steps [17‐20]. The 35 first step consists in sampling the ligand conformations in the active site of the protein receptor. The 36 second step involves the classification of these conformations by a scoring function. 37 The objective of these paper is to evaluate in silico anti‐pneumococcal activity of some 38 fluoroquinolone derivatives (Table 1) by using CLC Drug Discovery Workbench Software. Docking 39 studies have been conducted for all ligands and the docking scores were compared with the scores © 2019 by the author(s). Distributed under a Creative Commons CC BY license. Preprints (www.preprints.org)|NOTPEER-REVIEWEDPosted:30January2019 40 Table 1. The structure of the fluoroquinolone compounds. 2D Structure 3D Structure 2D Structure 3D Structure O O F CO2H F CO2H N N N N HN HN Cl NF: 1‐Ethyl‐6‐fluoro‐7‐(piperazin‐1‐yl)‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐carboxylic acid FPQ50:1‐Ethyl‐6‐fluoro‐7‐(piperazin‐1‐yl)‐8‐chloro‐1,4‐dihydro‐4‐oxo ‐quinoline‐3‐carboxylic acid C16H18FN3O3: M = 319.336 g/mol; m.p. = 218.3‐220.6˚C [25] C16H17ClFN3O3: M = 353.781 g/mol; m.p. = 227‐230˚C [25] O O F CO2H F CO2H N N N N N N Cl PF:1‐Ethyl‐6‐fluoro‐7‐(4‐methyl‐piperazin‐1‐yl)‐1,4‐dihydro‐4‐oxo ‐quinoline‐3‐ FPQ51:1‐Ethyl‐6‐fluoro‐7‐(4‐methyl‐piperazin‐1‐yl)‐8‐chloro‐1,4‐dihydro ‐4‐oxo‐quinoline‐3‐ carboxylic acid; C17H20FN3O3: M = 333.363 g/mol; m.p. = 269.2‐271.8˚C [26] carboxylic acid; C17H20ClFN3O3: M = 367.808 g/mol; m.p. = 219.6‐221.5˚C [26] O O F CO2H F CO2H N N N N . HCl HN HN Cl FPQ27: 1‐Ethyl‐6‐fluoro‐7‐(3‐methyl‐piperazin‐1‐yl)‐1,4‐dihydro‐4‐oxo ‐quinoline‐3‐ FPQ29.HCl: 1‐Ethyl‐6‐fluoro‐7‐(3‐methyl‐piperazin‐1‐yl)‐8‐chloro‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐ carboxylic acid; C17H20FN3O3: M = 353.781 g/mol; m.p. = 177.6‐180.6˚C [24] carboxylic acid. HCl C17H19ClFN2O3 . HCl: M = 353.781 g/mol; m.p. = 227‐230˚C [26] doi:10.20944/preprints201901.0307.v1 O O F CO2H F CO2H N N N N Cl FPQ35: 1‐Ethyl‐6‐fluoro‐7‐(pyrrolidin‐1‐yl)‐1,4‐dihydro‐4‐oxo‐quinoline ‐3‐ FPQ36: 1‐Ethyl‐6‐fluoro‐7‐(pyrrolidin‐1‐yl)‐8‐chloro‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐carboxylic carboxylic acid; C16H17FN2O3: M = 304.321 g/mol; m.p.= 336.6‐337.9˚C [25] acid; C16H16ClFN2O3: M = 338.766 g/mol; m.p. = 214.5‐217.8˚C [25] Preprints (www.preprints.org)|NOTPEER-REVIEWEDPosted:30January2019 3 of 15 O O F CO2H F CO2H N N N N Cl FPQ32: 1‐Ethyl‐6‐fluoro‐7‐(piperidin‐1‐yl)‐1,4‐dihydro‐4‐oxo‐quinoline ‐3‐carboxylic FPQ33: 1‐Ethyl‐6‐fluoro‐7‐(piperidin‐1‐yl)‐8‐chloro‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐carboxylic acid acid; C17H19FN2O3: M = 318.348 g/mol; m.p. = 202.4‐204.4˚C [26] C17H18ClFN2O3: M = 352.793 g/mol; m.p. = 187‐190˚C [26] O O F CO2H F CO2H N N N N Cl Q83: 1‐Ethyl‐6‐fluoro‐7‐(4‐methyl‐piperidin‐1‐yl)‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐ Q85: 1‐Ethyl‐6‐fluoro‐7‐(4‐methyl‐piperidin‐1‐yl)‐8‐chloro‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐ carboxylic acid; C18H21FN2O3: M = 332.37 g/mol; m.p. = 234.7‐237.1˚C [22] carboxylic acid; C18H20ClFN2O3: M = 366.815 g/mol; m.p. = 201‐202.5˚C [22] O O F CO2H F CO2H N N N N Cl FPQ24: 1‐Ethyl‐6‐fluoro‐7‐(3‐methyl‐piperidin‐1‐yl)‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐ FPQ30: 1‐Ethyl‐6‐fluoro‐7‐(3‐methyl‐piperidin‐1‐yl)‐8‐chloro‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐ carboxylic acid; C18H21FN2O3: M = 332.37 g/mol; m.p. = 188.1‐189.4˚C [23] carboxylic acid; C18H20ClFN2O3: M = 366.815 g/mol; m.p. = 163‐165.3˚C [24] O O F CO2H F CO2H doi:10.20944/preprints201901.0307.v1 N N N N O O Cl FPQ25: 1‐Ethyl‐6‐fluoro‐7‐(morpholin‐1‐yl)‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐carboxylic FPQ28: 1‐Ethyl‐6‐fluoro‐7‐(morpholin‐1‐yl)‐8‐chloro‐1,4‐dihydro‐4‐oxo‐quinoline‐3‐carboxylic acid; C16H17FN2O4: M = 320.32 g/mol; m.p. = 257.4‐258.7˚C [23] acid: C16H17ClFN2O4: M = 354.76 g/mol ; m.p. = 244.6‐246˚C [23] 41 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 30 January 2019 doi:10.20944/preprints201901.0307.v1 O F CO2H N N Cl 42 H2N 43 Figure 1. Clinafloxacin. 44 of standard drugs: Clinafloxacin (7‐[(3R)‐3‐aminopyrrolidin‐1‐yl]‐8‐chloro‐1‐cyclopropyl‐6‐fluoro‐4‐ 45 oxo‐1,4‐dihydroquinoline‐3‐carboxylic acid) (Figure 1). 46 2. Computational details 47 Molecular Docking studies have been realized with CLC Drug Discovery Workbench Software 48 to obtain accurate predictions on optimized conformations for both, the ligand (fluoroquinolone 49 compound) and their target receptor protein to form a stable complex. The fluoroquinolone 50 compounds have been synthesized in our laboratory [21‐26] and their 2D structure is shown in Table 51 1. The protein‐ligand complex has been realized based structure of Clinafloxacin (Figure 1) with 52 Streptococcus pneumoniae serotype 4 (strain ATCC BAA‐334/TIGR4) which was available through the 53 Protein Data Bank (PDB entry 3FOE) [28]. The score and hydrogen bonds formed with the amino 54 acids from group interaction atoms are used to predict the binding modes, the binding affinities and 55 the orientation of the docked ligands derivatives in the active site of the protein‐receptor. 56 2.1. Ligand preparation 57 The ligands, fluoroquinolone derivatives, have been prepared using SPARTAN’14 software 58 package [29]. Their molecular structures have been determined using DFT/B3LYP/6‐31 G* level of 59 basis set. In Table 2 are shown the electronic properties such as: HOMO (Highest Occupied Molecular 60 Orbital) and LUMO (Lowest Unoccupied Molecular Orbital) energy values, HOMO and LUMO 61 orbital coefficients distribution, molecular dipole moment, polar surface area (PSA), ovality, 62 polarizability, octanol water partition coefficient (log P), volume, area, number of hydrogen‐bond 63 donors (HBDs) and acceptors (HBAs). The DFT calculations were performed according to the 64 protocol described in our previous paper [30]. 65 2.2. Molecular docking studies 66 Molecular docking studies have been performed with CLC Drug Discovery Workbench Software to 67 obtain accurate predictions on optimized conformation for both, ligands and their target receptor 68 protein, as well to their resulted complexes. The protein‐ligand complex has been realized based on 69 the structure of Clinafloxacin with Streptococcus pneumoniae serotype 4 (strain ATCC BAA‐334/TIGR4) 70 assembly available from Protein Data Bank (PDB entry 3FOE). The docking simulations were 71 performed according to the docking protocol described in a previous paper [30], and involve the next 72 steps: setup the binding site and setup binding pocket in a Molecule Project, dock ligands imported 73 to a Molecule Table, inspect the docking results.
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