The document discusses in silico analysis and drug design to inhibit entry of the Ebola virus through the Niemann Pick C1 protein. Four FDA-approved drugs were studied that inhibit Ebola virus entry through late-stage inhibition. Docking studies showed BM15766 had the highest binding score to the NPC1 receptor. Scaffold modeling was then used to design 375 scaffolds, with scaffold 165 having the best score and proposed as a potential new antiviral drug.

1. In Silico analysis and drug designing to Inhibit Entry of Ebola
virus through Niemann Pick C1 Protein
Amol kunde
1
Fantasia Business Park, S-180, Corporate wing, sector - 30A, , Vashi, Navi Mumbai – 400705
2
Founder Director, M/S microSat Biolab , Fantasia Business Park, S-180, Corporate wing,
sector - 30A, Vashi, Navi Mumbai – 400705
Abstract:
Ebola virus (EBOV) is an enveloped RNA virus that causes hemorrhagic fever in
humans and non- human primates. No specific anti-Ebola viral agents are available. In
the present research 4 Food and Drug administration approved Drugs AY-9944,
Clomiphene, Bm15766, Amoliphene which inhibit EBOV entry at a late stage were
studied. All four are cationic amphiphiles that share additional chemical features like log
value, molecular weight and pka values. Docking studies were performed using the four
drugs as ligand and Niemann-Pick C1 (NPC1) as the receptor. BM15766 had the
highest E score value of hence this drug was used as a reference drug for designing the
scaffold, scaffold replacement studies were performed using Molecular operating
environment (MOE) software and a total of 375 scaffolds were designed, amongst that
scaffold pose no 165 was selected as a proposed drug which had the best E score
value of. From the present findings scaffold pose no 165 can be used in anti-filo viral th
Keywords: EBOV, CAD, NPC1,MOE
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Introduction: Computer aided drug design(CADD) is an emerging tool for research and
drug development process as it reduce the time taken for the process of drug
development and expense. Several new technologies have been developed and applied
in drug R & D to shorten the research cycle and to reduce the expenses. In computer
aided drug design process so many computational tools are used such as over viewing
tools, homology modeling, and homology modeling programs, molecular dynamics,
molecular docking and QSAR descriptors.[1]
CADD tools have been applied in almost every stage of drug R & D, greatly changing
the strategy and pipeline for drug discovery. CADD, from its traditional application of
lead discovery and optimization, has extended toward two directions: upstream
for target identification and validation, and downstream for preclinical study (ADMET

2. prediction).[2]
Ebola virus (EBOV) causes severe disease in humans and in nonhuman primates in the
form of viral hemorrhagic fever. This mysterious hemorrhagic fever was first described
in two separate 1976 outbreaks first in southern Sudan and subsequently in northern
Zaire, now Democratic Republic of the Congo. A causative agent was isolated from
patients in both epidemics and named Ebola virus after a small river in northwestern
Zaire[3]. Only years later did researchers recognize that the plagues were caused by
two distinct species of Ebola virus, Sudan Ebola virus and Zaire Ebola virus[4].

3. Methods: Four FDA drugs BM15766,AY9944,Clomiphene,Amolipene were obtained
from pubchem.Receptor 3GKI were taken from Protein data bank.Possible active site
were obtained from Q-site Finder.Molecular Dynamics and Simulation studies were
performed using VMD/NAMD.Four Drugs were Docked using AutoDock vina and
Molecular Operating Environment respectively and docking studies were
performed.Best structure were obtained from Docking studies , Scaffold were designed
by Molecular Operating Environment and best scaffold were obtained as a proposed
inhibitor.
Results and Discussion:
In this study two major findings have been presented. The first is that among all four
small molecules, there is a strict correlation between their chemical structures and their
abilities to induce cholesterol accumulation in LE/Lys, potently (>91%) block a late stage
of EBOV VLP entry, and block infection of replicating competent EBOV. All of the potent
inhibitors are CADs with similar MW, clogP, and pKa values, and most are class II
CADs with at least one tertiary amine group
Docking studies were performed and it was observed that the proposed inhibitor was
showing better result than the existing drug.BM15766 was selected as a reference Drug
and scaffold were desgined the E-score obtained from the Proposed Drug was -
Fig:Scaffold interaction with interacting residue fig:Pharmacophore mapping of propsed inhibitor
Here we can see 3 interaction of ligand with 3GKI receptor.
NH2 interacting with water ,water is getting attached with glutamic 171 and aspartic
128. oxygen is getting attched with lysine 67 NH intaercting with water, water is getting
attached with Arginine 172 and glutamic 171 .The proposed Scaffold shows better
interaction than the existing drugs.
Pharmacophore studies of propsed drug were performed using Ligandscout it was
observed that interaction of residues with receptors were mediated by properties like
hydrogen donor,ionization acceptor and receptor.
17.9703 which is even better than the reference drug.

4. References
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structure of the C-terminal domain of Ebola virus VP30 reveals a role in transcription
and nucleocapsid association. J Biol Chem 2002, 277:23186–23192
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C-terminal domain of Ebola virus VP30 reveals a role in transcription and nucleocapsid
association. J BiolChem 2003, 278:41830–41836
3) Falzarano, D.; Krokhin, O.; Wahl-Jensen, V.; Seebach, J.; Wolf, K.; Schnittler, H.J.;
Feldmann, H. Structure-function analysis of the soluble glycoprotein, sgp, of ebola virus.
Chembiochem 2006, 7, 1605–1611
4) Falzarano, D.; Krokhin, O.; Wahl-Jensen, V.; Seebach, J.; Wolf, K.; Schnittler, H.J.;
Feldmann, H. Structure-function analysis of the soluble glycoprotein, sgp, of ebola virus.
Chembiochem 2006, 7, 1605–1611