INTRODUCTION:

Mosquito borne diseases are major cause of morbidity and mortality across the subtropical and tropical regions, the disease spread by the bite of an infected mosquito not only malaria, but other diseases include chikungunya, dengue, zika, yellow fever, west nile and Japanese encephalitis.

In last three decades much progress in the control of malaria and other mosquito born infections but morbidity with associated infections remains high, whereas arbo-viruses-notably dengue, responsible for rise in disease severity, even in middle income countries that have almost eradicated malaria¹. Here I would like to discuss the new interventions and mode of actions as well as the compounds offer the reductions in disease burden. The number of malaria deaths worldwide remains 30 fold greater than dengue, but last decade there is increased mortality and morbidity for dengue due to lack of proper effective antiviral and monoclonal antibodies in the market². Arboviral infections caused substantial concern in last decade including chikungunya, followed by zika^3,4.

Historically, before World War II, repellants were types of smoke, tars, oils, and even camel urine. The oil of citronella, found in 1901; dialkylphthaltes in 1929, indalone in 1937, Rutgers612 in 1939. The general management of arthropods is prevention and if not, there are many counter act repellants available in the market approved by Environmental Protection Agency (EPA). The first effective against mosquitoes, gnats, chiggers, and bite fleas marketed was DEET in 1956, was slight yellowish oil, intended to be applied on the skin and cloths. The serious adverse effects at higher concentrations reported were seizures, agitation, uncoordinated movements, reduced blood pressure, and skin allergies hence lowest concentrations should be used. Next foremost used were permethrin found in 1973, effective pesticide and repellant, very long acting retain its potency for two weeks and applied specifically on cloths rather than skin^5–9. The next most popular safest synthetic compound was picaridin or icaridin found in 1998 and has been available in USA since 2005. Compared to icaridin, the DEET is a neurotoxin and absorbed into the body when applied on the skin and acts as plasticizer. The icaridin not considered as skin irritant but can cause mild to moderate eye irritation and reported as better efficacy with the minimum concentration about 20 percent where DEET at 30 percent and natural oils at 30 percent¹⁰. Ethylene hexanediol, was also reported has repellent property but currently banned due to evidence of developmental defects in animals¹¹. IR3535 or 3-{N-butyl-N-acetyl}-ethyl amino propionate, reported as insect repellant property in 1999 but not effective well as pervious compound and picaridin^12–14. Metofluthrin in 2006, chemically 2,3,5,6-tetrafluro-4-methoxy benzene designed based on QSAR studies of trans-Norchrysanthemic acid fluorobenzyl ester analogues and reported with high potency, being approximately thirty to forty times as potent as d-allethrin which used in preparation of mosquito coils, reported against mosquitoes in southern region or culex species¹⁵.

Fig. 1: The fundamental structural features common insect repellents

DEET-containing products may temporarily irritate the skin or eyes and repellents have been found to cause coughing and respiratory discomfort in users. They may irritate the digestive system and the stomach if consumed. Neurological effects have been documented, although they are uncommon and typically the result of mishaps or excessive exposure¹⁶. Products containing picaridin have been known to cause skin and eye discomfort in users. There have also been reports of vomiting¹⁷. IR3535 irritates the eyes and the skin when used undiluted, according to tests on humans and animals. Skin irritancy was not observed in experiments using diluted IR3535^18–21. Significant eye damage might result from using oil of lemon eucalyptus. After exposure, washing your eyes can lower your chance of long-term damage. In research on animals, it has been connected to skin irritation. Rats given lemon eucalyptus oil had problems moving around. They were also sluggish and experienced breathing changes¹¹. To establish a connection between drugs and cancer, agencies consult numerous studies. The DEET component is not classifiable as to human carcinogenicity, according to the EPA. This shows that there hasn't been enough conclusive research to say whether it's likely to cause cancer. The risks of cancer associated with other common repellent active components have not been thoroughly evaluated^12-21. However, if a chemical alters genes or cell DNA in a lab setting, this may be one indication that it's associated with cancer. In lab experiments, none of the usual repellant chemicals have been demonstrated to harm DNA^{10,22,22–24}. Repellants with EPA registration may be used during pregnancy and while nursing, according to the CDC. Repellents may lower risks from diseases spread by insects that could harm a newborn in development. For pregnant women in locations where there is a danger of zika, the American College of Obstetricians and Gynecologists (ACOG) advised by an EPA-registered repellent with DEET²⁵. Approximately 3–19% of repellents applied to skin may be absorbed by the body. Combining sunscreen and insect repellant may change how well those chemicals are absorbed by your skin. Combining the two can improve skin absorption of the repellant. However, which sunscreen and which repellent are utilized will determine the consequences of using both. Studies on the use of IR3535 or oil of lemon eucalyptus with sunscreens are scarce or nonexistent. There is conflicting data connecting DEET exposure to seizures in children²⁶. There hasn't been much research done on how repellents break down in the air, water, and soil. Picaridin and DEET breakdown periods in soil or water have been reported to vary and can take days, weeks, or even longer and for birds, fish, and aquatic invertebrates somewhat harmful^27,28. Birds, fish, and aquatic invertebrates are essentially unaffected by picaridin's toxicity. There aren't many studies on the toxicity of IR3535 and oil of lemon eucalyptus to fish and birds. Small concentrations of DEET and picaridinin naturally occurring waters have not been proven to have any negative effects on small organisms like snails, mayflies, or water fleas²⁹. An insect must meet the treated object to be injured or killed by permethrin, should not be used as a repellent on the skin and certain permethrin-containing products can be used to treat fabrics. Only a very little amount of the compound transmitted onto skin from treated fabric, therefore exposure when wearing treated clothing is likely to be modest as well as which does not absorb well via skin and applying to garments while it is being worn is not advised. Use only products that have specific instructions for treating fabrics to treat clothing, netting, or equipment. Avoid over treating fabrics. For treatment, use the appropriate concentration. Before handling or wearing any treated objects, allow them to completely dry following treatment ^30–33. Hydrocarbon combinations found in the essential oils of several plant species have been observed to be excellent pest repellents. It has been discovered that the monoterpenoids, which make up most of the components, are cytotoxic to plant and animal tissue, compromising the proper operation of these tissues.

Fig.2 Structures of some synthetic and natural repellents

Plant-based-pesticides are becoming more popular as an alternative to chemical ones since they are more readily available and have a smaller negative impact on the environment^34–38. Here, we would like to discuss the different theories on mode of actions, efficacy and establishing novel molecules for future research aiming at repellant action.

RESULTS AND DISCUSSION:

The first crystal structure of an olfactory macromolecule with a repellent was found in the complex of anopheles gambiae-odorant Binding Protein-1 was the most potent insect repellent was DEET. This discovery opened the door for OBP1-structure based methods for the discovery of new structurally based disruptors. in this study majorly to be focused on the different targets like Odorant binding protein from Anopheles gambiae culex-AgamOBP1, quinquefasciatus-cquiOBP and aedes aegypti-aaegOBP1.

The biochemical target for AgamOBP1 as 3N7H³⁹ and the binding protein (OBP) from the A. gambiae mosquito is shown here in its 1.5A crystal structure. Insect odorant binding proteins are the first olfactory system elements to encounter as well as proven as repellent though Odors coming from different sources for presentation to olfactory receptors, which then initiate the appropriate signal transduction cascades that result physiological and behavioural responses. We found that DEET attaches on the border of a long hydrophobic tunnel by exploiting many non-polar contacts and one hydrogen bond, which is thought to be critical for its identification.

Based on the experimentally determined affinity of Agam-OBP1 for the ligand (K(d) of 31.3 M) and our structural data, we modelled the interactions for this protein with 29 promising leads reported in the literature to have significant repellent activities and carried out fluorescence binding studies with four highly ranked ligands.The viruses that cause filariasis, West Nile virus, St. Louis encephalitis, and other illnesses are transmitted to humans by culex mosquitoes and chosen the target as cquiOBP-3OGN⁴⁰.An automated server for docking analysis is Patchdock. In structural biology, automated prediction of macromolecule and small molecule interactions is frequently employed since it allows for high-accuracy predictions and they use for the prediction of six-dimensional transformation space is dependable and effective for protein-ligand interactions^41–47.To create poses for a group of protein–ligand complexes for that the crystal-structure is to be known and three docking programmes like AutoDock Vina were employed.

The new standard is based on the real space R-factor (RSR), which assesses how well a collection of atoms—in this case, the ligand—fits the observed electron density by comparing the experimental electron density to the expected density predicted by the model (i.e., the predicted ligand poses).The usual standard, the root-mean-square distance (RMSD) between the docking pose and the binding configuration in the crystallographic model, is contrasted with the RSR-based metric. The majority of residues at chain A, including Leu71, Leu78, His51, Ala87, Met90, Gly98, Lys91 and Leu96, make hydrophobic interactions with the ligands, according to the crystallographic structure of AgamOBP1 complexed with DEET. All the physicochemical properties such number of groups able to make hydrogen bonds with targets like OH, NH groups and lipophilicity nature was discussed in Table 1 and PatchDock scores and docking scores influences binding ability were presented in Table 2 and 3.

Table 1: Physicochemical properties of the selected molecules

S. No	Repellent	Mol. Formula	M.Wt	nON	nOHNH	miLogP	nrotb	HBA	HBD	n Violation
1	DEET	C₁₂H₁₇NO	154.25	2	0	2.34	3	2	0	0
2	Picaridin	C₁₂H₂₃NO₃	229.32	4	1	1.41	5	4	1	0
3	IR3535	C₁₁H₂₁NO₃	215.29	4	0	0.76	8	4	0	1 Rotors>7
4	Citronellal	C₁₀H₁₈O	154.25	1	0	2.25	5	1	0	0
5	Permethrin	C₂₁H₂₀Cl₂O₃	391.28	3	0	4.43	7	3	0	1 (MLOGP>4.15)
6	p-menthane-3, 8-diol	C₁₀H₂₀O₂	172.27	2	2	0.84	1	2	2	0
7	Thymol isovalerate	C₁₉H₂₆O₅	334.41	5	0	2.65	9	5	0	1 Rotors>7
8	Carvacrol acetate	C₁₂H₁₆O₂	192.25	2	0	3.13	3	2	0	0
9	P-anisyl hexanoate	C₁₄H₂₀O₃	236.31	3	0	2.78	8	3	0	1 Rotors>7
10	Metofluthrin	C₁₈H₂₀F₄O	360.34	6	1	4.55	7	7	0	1 (MLOGP>4.15)

Table 2: Calculated binding free energies calculated by In silico methodology Patch Dock Score for the targets [3OGN/3N7H]

S. No	Repellent	3OGN			3N7H
S. No	Repellent	SCORE	AREA	ACE	SCORE	AREA	ACE
1	DEET	4026	454.3	-254.53	4082	467.5	-315.10
2	Picaridin	3708	413.0	-121.95	3708	413.0	-121.95
3	IR3535	4044	467.4	-152.03	4180	445.3	-221.07
4	Citronellal	3978	432.3	-140.63	1039	442.0	-22.31
5	Permethrin	4272	538.9	-274.44	4630	517.5	-376.90
6	P-menthane-3,8-diol	4440	529.9	-240.08	4888	557.9	-319.05
7	Thymol isovalerate	4380	531.4	-176.91	4754	524.0	-264.87
8	Carvacrol acetate	4516	568.3	-258.35	4814	530.5	-147.34
9	P-anisyl hexanoate	5212	569.9	-152.16	5404	637.5	-252.44
10	Metofluthrin	4125	745.2	-198.09	3542	429.0	-213.61

Based on the molecular docking simulations against culex quinquefasciatus, pdb code: 3OGN, revealed that Permethrin was potent repellent with the binding energy -10.80 k.cal per mol followed by Metofluthrin with the binding anergy -8.55 k.cal per mol, standard compound DEET reported about -7.20 k.cal per mol. Permethrin with the various binding sites interacting with target amino acids like MET 91, ALA 98, LEU73, 80, H-Bonding with TYR 122, PHE 123, LEU124 and TRP114, LEU73 hydrophobic interactions. metofluthrin H-Bonding with target residues LEU15, HIS111, LEU68, ALA62, LEU124 and hydrophobic interactions with residues like LEU80, MET91, LEU76 and LEU22 (Table 3).

The compound permethrin against AgamOBP1also revealed potent binding orientations with the -10.55 followed by metofluthrin -9.67 k.cal per mol, even these were more potent than standard DEET, reported about -7.36 k.cal per mol.Patch Dock Score for the targets3OGN and 3N7H revealed the same compounds were potent binding energies value of Access Control Entry (ACE) reported. Permethrin reported against Aedes aegypti, pdb code: 3K1E, about -11.40 k.cal per mol highest binding energy among all the NPs, H-Bonding in LUE73, TRP114, GLY92, HIS77, LEU89 and many hydrophobic bonding and followed by Metofluthrin with the second highest binding anegy with the targets about -8.90 k.cal per mol, even in comparison with the standard compound DEET reported about -7.44 k.cal per mol and all the study contributed most energetically to the stability of the ligand in the AgamOBP1 binding pocket (Figure-3and 4).

The AgamOBP1 chain B residues, on the other hand, had just a small contribution to the stability of the ligand, and the interaction with Met89, Lys93, and Leu96 that we noticed was the most significant for ligand binding.

Table 3: Calculated binding free energies calculated by Molecular Docking

S. No	Repellent	Binding Score ΔG (kcal mol^–1)
	Repellent	3N7H	3OGN	3K1E
1	DEET	-7.36	-7.20	-7.44
2	Picaridin	-6.65	-6.47	-7.03
3	IR3535	-6.20	-5.81	-6.60
4	Citronellal	-7.32	-6.28	-8.25
5	Permethrin	-10.55	-10.80	-11.40
6	P-menthane-3,8-diol	-5.36	-6.45	-7.12
7	Thymol isovalerate	-7.05	-7.90	-4.72
8	Carvacrol acetate	-6.30	-7.90	-6.15
9	P-anisyl hexanoate	-6.35	-7.04	-8.10
10	Metofluthrin	-9.67	-8.55	-8.90

EXPERIMENTAL:

The approach used to study the interactions between two molecules is known as molecular docking.

The macromolecule serves as the protein receptor in this process. The ligand molecule, which can function as an inhibitor, is a micromolecule the steps including following.

I) Protein data bank (PDB) should be used to get the three-dimensional structure of the protein 3N7H, 3OGN, 3K1E were chosen and downloaded in pdb formats for studies and that should then be pre-processed according to the provided parameters, removal water molecules from void, stabilizing the charges, restoring the missing residues, and creating side chains etc.II) Active site prediction, when protein has been prepared, the active site of the protein should be identified and the receptor may have several active sites; nevertheless, just the one that is of concern should be chosen⁴⁵. When present, hetero atoms and water molecules are most often eliminated using Discovery studio visualizer⁴⁶.

III) The third step is the preparation of the ligand, which may be done by retrieving it from a wide range of databases like ZINC or PubChem or by drawing it using the Chemsketch tool and were modified into pdb formats by openbabelto do the docking studies. After docking the ligand against the protein, the interactions are examined. The scoring function awards points based on the selection of the best docked ligand complex. A potent molecule must be present at the target site in the body in a bioactive state for a long enough period for the expected biologic activities to take place for it to be effective as a medication. To create new drugs, it is necessary to evaluate absorption, distribution, metabolism, and elimination (ADME) at progressively earlier stages of the discovery process, when the number of possible compounds is high but physical sample access is limited. In that situation, computer models are appropriate substitutes for experimentation.

CONCLUSION:

Based on discoveries from the literature, it has been stated that plants are the plenty of sources of repellant properties and are using still in many parts of the world. Natural products are thought to be safer for human usage than synthetic ones. Furthermore, natural repellents are typically straightforward, affordable, and available to communities with little outside assistance, in contrast to synthetic repellents that pose environmental threats, have lethal effects on organisms that are not their targets. Chemoinformatic developments have enabled the building of virtual screening-capable chemical libraries for lead finding. Additionally, computer techniques are being created to forecast a compound's drug-likeness properties. While lead discovery identifies novel chemical compounds that act on certain targets, target discovery aims to identify and validate appropriate pharmacological targets for therapeutic intervention. One can get the conclusion that based on the molecular docking simulations against culex quinquefasciatus, 3OGN, revealed that permethrin was potent repellent with the binding energy -10.80 k.cal per mol followed by metofluthrin with the binding anergy -8.55 k.cal per mol, permethrin reported against Aedes aegypti, 3K1E, about -11.40 k.cal per mol highest binding energy followed by metofluthrin with the second highest binding anegy with the targets about -8.90k.cal per mol, permethrin reported against AgamOBP1also revealed potent binding orientations with the -10.55 followed by metofluthrin -9.67k.cal per mol, conclude that these compounds were potent and safest natural compounds in even than standard DEET, which was toxic in equipotent concentrations of the evidenced NPs.

AUTHOR INFORMATION:

Sathish Kumar Mittapalli, ORCID: https://orcid.org/my-orcid?orcid=0000-0002-2028-2936

R. Parameshwar, ORCID: https://orcid.org/0000-0001- 7049-0111

ACKNOWLEDGMENTS:

The authors would like to thank the management of Amity University, Madhya Pradesh, Gwalior for giving an opportunity to carry out this research.

CONFLICT OF INTEREST:

No conflict of interest was declared by the authors.

ABBREVIATIONS:

3D: Three Dimensional

3K1E: Protein code for Aedes Aegypti

3OGN: Protein code for Culex Quinquefasciatus

3V2L and 3R1O: Protein code for Anopheles Gambiae

ACOG: American College of Obstetricians and Gynecologists

ADMET: Absorption, Distribution, Metabolism, Excretion, and Toxicity

DEET: N, N-Diethyl-meta-toluamide

DNA:Deoxyribo Nucleic Acid

EPA: Environmental Protection Agency

EssOilDB: Essential Oil Database

FDA: The United States Food and Drug Administration

GRs: Gustatory Receptors

IR3535: 3-{N-butyl-N-acetyl}-ethyl amino propionate

M.Wt: Molecular Weight

MD: Molecular Dynamics

miLogP: Lipophilicity

nOHNH: Number of hydroxyl and amino groups

nON: Number of Oxygen and Nitrogen atoms

NPs: Natural Products

nrotb: Number of rotatable bonds

OBPs: Odorant Binding Proteins

ORNs: Olfactory receptor neurons

PBPK/PD: Physiologically Based Pharmacokinetic/PharmacoDynamic

PKUDDS: Peking University Drug Design System

QSAR: Quantitative Structure-Activity Relationship

TRPA-1: Transient Receptor Potential Ankyrin 1

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Received on 26.05.2023 Modified on 11.10.2023

Asian J. Research Chem. 2024; 17(1):17-24.

DOI: 10.52711/0974-4150.2024.00004

Virtual Screening and Pharmacophore Modeling for discovery of Biologically Active Natural Products as Inhibitors of Odorant-binding Proteins

Sathish Kumar Mittapalli¹*, J N Narendra Sharath Chandra², Jay Prakash Soni¹, Ram Babu Tripathi¹, Iffath Rizwana²

INTRODUCTION:

Virtual Screening and Pharmacophore Modeling for discovery of Biologically Active Natural Products as Inhibitors of Odorant-binding Proteins

Sathish Kumar Mittapalli1*, J N Narendra Sharath Chandra2, Jay Prakash Soni1, Ram Babu Tripathi1, Iffath Rizwana2

INTRODUCTION:

Sathish Kumar Mittapalli¹*, J N Narendra Sharath Chandra², Jay Prakash Soni¹, Ram Babu Tripathi¹, Iffath Rizwana²