VIRTUAL SCREENING OF NEWER POTENTIAL COLONY STIMULATING FACTOR 1 INHIBITORS AS POTENT ANTIEPILEPTIC AGENTSHTML Full Text
VIRTUAL SCREENING OF NEWER POTENTIAL COLONY STIMULATING FACTOR 1 INHIBITORS AS POTENT ANTIEPILEPTIC AGENTS
R. Priyadharsini * A. Dharuman, P. Nithya, P. Shalini and G. Sumithra
College of Pharmacy, Madras Medical College, Chennai - 600003, Tamil Nadu, India.
ABSTRACT: Background: Epilepsy is a chronic disorder that causes unprovoked, recurrent seizures like a sudden rush of electrical activity in the brain. Neuronal hyperexcitability in epilepsy is due to an imbalance between glutamate-mediated excitation and GABA-mediated inhibition. Aim: This prompted us to design newer CSF1R inhibitors as efficient therapeutic drugs for the treatment of epilepsy. Materials and Methods: Based on the common pharmacophoric features for the inhibition of CSF1R inhibitors, a series of leads were designed using computational methods. A virtual library consisting of newly designed 60 molecules as CSF¬1R inhibitors were constructed .Based on these facts, a virtual library has been generated with 60 newly designed ligands containing imidazole, benzo pyrrole, quinoline, oaxzole, quinoxaline, benzimidazole, heterocyclic nucleus as CSF1R inhibitors (60). The binding mechanism of newly designed ligands with target enzymes CSF1R inhibitors was studied using Auto dock tools 1.5.6. Conclusion: The designed compounds were subjected and filtered by applying ADMET properties. In comparison with docking scores of standard antiepileptic drugs vigabatrin (GABA-2.14, CSF1R-1, 31) and sodium valproate (GABA-3.19, CSF1R-3.6) and the newly designed ligands, CS1 (-6.61), CS3 (-6.22), CS14 (-6.04) were found to be highly active hits than that of standards.
Epilepsy, CSF1R inhibitors, ADMET properties, Docking studies
INTRODUCTION: The word Epilepsy means "seizure disorders", the fourth most common neurological disorder which affects people of all ages. Epilepsy is a chronic disorder that causes unprovoked, recurrent seizures like a sudden rush of electrical activity in the brain 1. For 6 in 10 people, the cause of a seizure can’t be determined. Between 15 to 30 percent of children with intellectual disabilities have epilepsy. Between 30 and 70 percent of people who have epilepsy also have depression, anxiety, or both. Neuronal hyperexcitability in epilepsy is due to an imbalance between glutamate-mediated excitation and GABA-mediated inhibition.
The symptoms of epilepsy are seizures, staring blankly, unresponsiveness, performing repetitive movements, biting of the tongue, loss of conscious-ness. Colony-stimulating factor 1 receptor (CSF1R), also known as macrophage Colony-stimulating factor receptor (M-CSFR) is a cell-surface protein encoded in humans, by the CSF1R gene (also known as c-FMS). It is a receptor for a cytokine called colony-stimulating factor 1. The main aim of the study is to identify novel, safe and effective newer antiepileptic agents with good predicted capability to inhibit the Colony Stimulating Factor 1 Receptor using Computational Drug Designing methods.
MATERIALS AND METHODS:
Selection of Target: Approximately one in three epilepsy patients are resistant to all currently available antiepileptic drugs (AEDS) and none of the current drugs are disease-modifying or curative which targets cell membrane receptors.
In order to connect module expression to cell membrane receptors, the colony-stimulating factor 1 receptor was identified as a novel therapeutic target for the treatment of epilepsy. The targets creating the greatest enthusiasm at this time for the treatment of epilepsy include colony-stimulating factor 1 receptor. Some of the recent and efficient PDB file receptors for the treatment of Epilepsy with low resolution were selected and further evaluated by their resolution value (R-value), optimized crystal ligand, and interaction details. Some of the selected receptors listed below from which the highlighted best PDB target was selected for the present study.
The active amino acid binding sites for the selected PDB (3BEA) of the CSF1R target were identified by reviewing the journals.
TABLE 1: LIST OF PDB FOR CSF1R TARGET FOR EPILEPSY
|S. no.||Code||Resolution (Ao)||S. no.||Code||Resolution (Ao)|
TABLE 2: ACTIVE AMINO ACID SITE OFCSF1R TARGET
|Receptor||PDB Code||Active Amino Acid Binding Sites|
|CSF1R||3BEA||Cys 666 (A), Glu 664 (A), Ala 614 (A), Leu 588 (A), Asp 802 (A), Arg 801(A), His 899 (A), Lys 586 (A), Tyr 665 (A), Gln 547 (A), Arg 816 (A), Gln 920 (A), Lys 883 (A), Pro 882 (A), Gln 913 (A), Phe 563 (A), Thr 562 (A), Asp 565 (A), Tyr 561 (A), Cys 666 (A), Lys 574 (A), Val 811 (A), Val 861 (A), His 757 (A), Tyr 575 (A), Leu 649 (A), Gln 642 (A), Gln 576 (A), Leu 650 (A), Arg 801 (A), Gln 904 (A), Ala 767 (A), Phe 903 (A), Glu 884 (A), Thr 563 (A), Asp 570 (A), Arg 816 (A), Gln 547 (A), Leu 799 (A), Thr 833 (A), Tyr 546 (A).|
Pharmacophoric Identification: A Pharma-cophore is defined as a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecule's biological activity 38. Hence, all these chemical features were used as 3D structural query to screen the chemical database for retrieving new potent CSF1R inhibitors.
Database Screening: Based on the above quoted literature facts in designing potent CSF1R inhibitors, the target screening library was designed by using molecular fragments from a relatively narrow and low molecular weight range (300-5000D), selected diversity at both the putative “scaffold” core.
The analogue library was generated by modifying the respective functional groups with sterically and conformationally allowed substituent’s using the reagent database and a computational design model.
Virtual Library: A virtual scaffold library consisting of newly designed 60 molecules has CSF1R inhibitors has been constructed.
Drug Likeness Screening: Drug likeness is a qualitative concept used in drug design for how a drug-like substance is to be an effective drug. Drug likeness properties were performed for all the newly designed CSF1R inhibitors using different online software like Lipinski's rule of five, Osiris online software, Mol inspiration software, and the results tabulated.
Docking Studies: All the designed ligands were subjected to docking studies using Auto dock tools 1.5.6 software, and the results were discussed below. Auto dock tools 1.5.6 are a molecular modeling simulation, especially effective for protein-ligand docking.
RESULTS AND DISCUSSION: In search of new and potent CSF1R inhibitors as antiepileptic agents, a virtual scaffold library of 60 molecules was constructed using chem sketch by reviewing efficient articles and journals and based on features such as HBA, HBD, and HYP Pharmacophoric features.
TABLE 3: PHARMACOPHORIC FEATURES USED IN CONSTRUCTION OF LIBRARY OF CSF1R INHIBITORS
|Imidazole, Thiadiazole, Benzimidazole, Aminothiazole, Phenolic-OH, Aniline, Alkyl amines, Oxazole, Morpholine.||C=O of aliphatic and aromatic amides, C=O of aromatic ketones, C=O of diamide||Phenyl, Biphenyl, Diazole, Pyridine, Triazole, Quinaxoline, Tolyl, Dimethyl benzene|
VIRTUAL LIBRARY OF CSF1R INHIBITORS
Drug Likeness Screening: The newly designed ligands were subjected to molecular docking, ADMET properties, and Lipinski rule of five, toxicity prediction. Through this, the newly generated ligands are filtered and refined, which constitutes optimization of leads. The compounds having better-estimated activity value and drug-like properties are filtered and considered for further molecular docking.
TABLE 4: LIPINSKI, S RULE OF FIVE FOR THE CSF1R INHIBITORS
|Compound||Log P||Mol. Wt||Tpsa||Nohnh||Non||No. of Rotatable Bonds||No. of Violations|
Toxicity: Thus, all newly designed ligands (CSF1R inhibitors) have satisfied all the above filtering method of good predictive activity with good docking scores and also drug-likeness properties confirming that these molecules are accepted to be orally bioavailable.
Docking Studies: Auto dock tools 1.5.6 is a molecular modeling simulation, especially effective for protein-ligand docking. Based on docking scores, all the newly designed ligands were categorized as highly active, moderately active, and low active hits as below. Based on docking scores, all the newly designed ligands were categorized as highly active, moderately active, and low active hits as below.
TABLE 4: LIST OF DOCKING SCORE FOR DESIGNED CSF1RLIGANDS (AUTODOCK 1.5.6)
|Ligand||Docking Score||No. of Interactions||Hydrogen Bond Interaction|
|CS1||-6.61||7||i) Nitrogen of benzoxazine group with Cys666.|
|CS2||-4.12||1||i) Nitrogen of benzamide group with His899.|
|CS3||-6.22||4||i) Oxygen of carbonyl group with Lys586.|
|CS4||-4.41||2||i) NH group with Gln547.
ii) Oxygen of carbonyl group with Arg816
|CS5||-4.62||2||i) Oxygen of methoxy group with Gly605.
ii) NH group with Lys574.
|CS6||-5.07||3||i) Oxygen of hydroxyl group with Ala800
ii) Oxygen oxadiazole group with Cys666.
|CS7||-4.92||4||i) Oxygen of methoxy group of Lys883.
ii) Oxygen of carbonyl group with Gln913.
|CS8||-3.34||5||i) Oxygen of carbonyl group with Asp565
ii) Quinoline group with Tyr561
|CS9||-3.5||4||i) Nitrogen group of Methyl benzamide group with Lys574|
|CS10||-5.05||2||i) Oxygen of carbonyl group with Tyr665|
|CS11||-4.38||6||i) Nitrogen of pyridazine group with Cys883|
|CS12||-4.44||1||i) Oxygen of Benzofuran group with Lys574|
|CS13||-4.28||3||i) Hydroxyl group with Glu554
ii) NH group with Leu588
|CS14||-6.04||4||i) N of Indole group with Glu664|
|CS15||-4.73||6||i) NH group with Gly603|
|CS16||-3.38||5||i) Oxygen of carbonyl group with Val834
ii) Nitrogen of pyrazole group with Glu554
|CS17||-3.19||7||i) NH group with Lys574
ii) Nitrogen of pyrazole group with Glu554
|CS18||-3.38||3||i) Nitrogen of pyrazole group with Arg801|
|CS19||-3.15||2||i) Nitrogen of pyrazole group with Val811
ii) Oxygen of carbonyl group with Val811
|CS20||-4.29||5||i) Oxygen of carbonyl group with Ser632
ii) Hydrogen group with Arg549
|CS21||-3.53||3||i) Hydrogen group with Glu554
ii) Oxygen of carbonyl group with Lys551
|CS22||-3.75||3||i) Hydroxyl group with Arg816
ii) N of pyrazole group with Val861
|CS23||-3.55||4||i) NH group with Gly789|
|CS24||-3.72||3||i) NH Group with Ala879|
|CS25||-3.92||5||i) Oxygen of carbonyl group with Ala592
ii) Nitrogen of pyrazole group with Arg816
|CS26||-4.34||3||i) Hydroxyl group with Ser555
ii) Hydroxyl group with Asn773
|CS27||-4.38||3||i) NH group with Phe880|
|CS28||-4.96||4||i) Ethoxy group with Tyr665|
|CS29||-4.28||5||i) NH group with Ala767
ii) Oxygen of carbonyl with Phe903
|CS30||-5.3||4||i) Hydroxyl group with Asp670|
|CS31||-4.68||2||i) Oxygen of carbonyl group with Glu858|
|CS32||-4.42||6||i) Oxygen of carbonyl group with Gly858
ii) Hydrogen of Indole group with Val861
|CS33||-4.93||5||i) Hydroxyl group with Arg816
ii) Oxygen of carbonyl group with Gln574
|CS34||-4.75||4||i) Nitrogen and Oxygen of Benzoxazine group with Tyr556|
|CS35||-4.75||7||i) NH group with Gln835
ii) Oxygen of benzoxazine group with Tyr833
|CS36||-5.03||6||i) Hydroxyl group with Tyr556
ii) Oxygen and Nitrogen of benzoxazine group with Gln904
|CS37||-4.83||2||i) Oxygen of benzoxazine group with Lys606
ii) Oxygen of carboxyl group with Thr787
|CS38||-4.64||6||i) Hydroxyl group with Cys666
ii) Nitrogen of benzimidazole group with Leu588
|CS39||-4.86||5||i) Oxygen of carbonyl group with Tyr668|
|CS40||-4.85||4||i) Nitrogen of benzimidazole group with Asn814|
|CS41||-4.4||4||i) Oxygen of carbonyl group with Glu835
ii) Nitrogen of benzimidazole group with Glu835
|CS42||-4.1||5||i) Hydroxyl group with Gln642
ii) Nitrogen and Oxygen of oxazole group with Gls605
|CS43||-4.95||4||i) Oxygen and Nitrogen of oxazole group with Asp802
ii) NH group with Ala800
|CS44||-5.38||5||i) Nitrogen of oxazole group with Asp802|
|CS45||-4.23||2||i) NH group with Glu576|
|CS46||-4.82||3||Hydroxyl group with Asp802|
|CS47||-5.13||3||i) NH group with Ala800|
|CS48||-5.73||3||i) NH group with Ala800|
|CS49||-4.34||1||i) Nitrogen of pyrazole group with Leu588|
|CS50||-4.47||4||i) Oxygen of carbonyl group with Lys793
ii) NH group with Glu664
|CS51||-4.91||3||i) Oxygen of carbonyl group with Lys586|
|CS52||-4.13||3||i) Oxygen of pyridoxazine group with Lys678|
|CS53||-4.37||3||i) Oxygen of carbonyl group with Val811
ii) Oxygen of pyridoxazine group with Lys820
|CS54||-4.18||3||i) Oxygen of carbonyl group with Lys574|
|CS55||-4.65||5||i) Nitrogen of pyridoxazine group with Lys574|
|CS56||-4.44||4||i) Oxygen of pyrazole group with Gls605|
|CS57||-5.6||5||i) Oxygen of carbonyl group with Lys616
ii) Nitrogen of Naphthyridine group with Leu588
|CS58||-4.71||4||i) Nitrogen atom with Gln 904|
|CS59||-4.83||6||i) Nitrogen of naphthyridine group with Lys574
ii) NH group with Lys574
|CS60||-4.26||2||i) Oxygen of carbonyl group with Gln835|
|GABA||-3.19||9||i) Keto group with Lys 48
ii) OH group with Leu 50
|CSF1R||-3.6||2||i) keto group with Arg 777
ii) OH group with Arg 649
|Vigabatrin||GABA||-2.14||4||i) NH2 Group with Glu 17
ii) NH2 Group with Tyr 5
|CSF1R||-1.31||2||i) NH2 Group with Glu 554|
TABLE 5: DOCKING RESULTS OF CSF1R INHIBITORS USING AUTODOCK TOOLS 1.5.6
|S. no.||Receptor||Highly Acting (>6)||Moderately Acting (4-6)||Low Acting (<4)|
|1.||CSF1R Inhibitors||CS1,CS3,CS14||CS2, CS4, CS5, CS6, CS7, CS10, CS11, CS12, CS13, CS15, CS20, CS26, CS27, CS28, CS29,
CS30, CS31, CS32, CS33, CS34, CS35, CS36,
CS37, CS38, CS39, CS40, CS41, CS42, CS43,
CS44, CS45, CS46, CS47, CS48, CS49, CS50,
CS51, CS52, CS53, CS54, CS55, CS56, CS57,
CS58, CS59, CS60
|CS8, CS9, CS16,
CS17, CS18, CS19,
CS21, CS22, CS23,
CONCLUSION: Virtual screening of the Molecular chemical database has revealed that all the 60 newly designed CSF1R inhibitors containing hydrogen bond acceptor lipid (HBAL), hydrogen bond donor (HBD), hydrophobic (HYP) features have a crucial role in the treatment of epilepsy. Nearly 20 proposed ligands were found to be effective in inhibiting CSF1R by exhibiting two hydrogen bond interactions. In comparison with docking scores of standard antiepileptic drugs Vigabatrin ( GABA-2.14,CSF1R-1.31) and Sodium valproate (GABA-3.19, CSF1R -3.6) and the newly designed ligands, CS1 (-6.61), CS3 (-6.22), CS14 (-6.04) were found to be highly active hits than that of standard. Hence, we propose that the final lead compounds like CS1 (3-methyl-N-(4-propanoyl-phenyl) - 4H - 1, 2-benzoxazine-7-carboxamide), CS3(7-methyl-N-(4-propanphenyl)-4a-8a-dihydro 2H-pyrano[2,3-b] pyridine-3-carboxamide), CS14 (3-methyl – N - (4 - propanoylphenyl) - 1H - indole-5 carboxamide) as a possible virtual leads to design novel CSF1R inhibitors which can be synthesized and evaluated for in-vitro and in-vivo antiepileptic screening further, in future studies.
ACKNOWLEDGEMENT: We consider this as an opportunity to express our sincere thanks to The Dean, Our Principal, and Our Guide, College of Pharmacy, Madras Medical College, Chennai-03.
CONFLICTS OF INTEREST: Nil
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How to cite this article:
Priyadharsini R, Dharuman A, Nithya P, Shalini P and Sumithra G: Virtual screening of newer potential colony stimulating factor 1 inhibitors as potent antiepileptic agents. Int J Pharm Sci & Res 2021; 12(3): 1939-49. doi: 10.13040/IJPSR.0975-8232.12(3).1939-49.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
R. Priyadharsini * A. Dharuman, P. Nithya, P. Shalini and G. Sumithra
College of Pharmacy, Madras Medical College, Chennai, Tamil Nadu, India.
09 September 2019
28 December 2020
18 February 2021
01 March 2021