VIRTUAL SCREENING OF NEWER POTENTIAL COLONY STIMULATING FACTOR 1 INHIBITORS AS POTENT ANTIEPILEPTIC AGENTS

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 (AED_S) 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

TABLE 2: ACTIVE AMINO ACID SITE OFCSF1R TARGET

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.

Lead Optimisation:

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

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

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 Results:

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)

TABLE 5: DOCKING RESULTS OF CSF1R INHIBITORS USING AUTODOCK TOOLS 1.5.6

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.

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