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Analog designing & target idendification of collagenase in wound healing.

Introduction

Healing of Wound is a chain of process necessary for the removal of invaded pathogens from the damaged tissue of the body for completion partial remodeling of injured tissue (Clark., 1985; Goepel., 1996; Matusda et al., 1998; Micera et al., 2001). The wound healing process has 3 phases. They are the inflammatory phase, the proliferative phase, and the maturational phase. The inflammatory phase is characterized by hemostasis and inflammation. Collagen exposed during wound formation activates the clotting cascade (both the intrinsic and extrinsic pathways), initiating the inflammatory phase. After injury to tissue, the cell membranes, damaged from the wound formation, release thromboxane A2 and prostaglandin 2-alpha, potent vasoconstrictors. This initial response helps to limit hemorrhage. After a short period, capillary vasodilatation occurs secondary to local histamine release, and the cells of inflammation are able to migrate to the wound bed. The timeline for cell migration in a normal wound healing process is predictable. (Cohen., 1992)

The inflammatory phase continues, and more immune response cells migrate to the wound. The second response cell to migrate to the wound, the neutrophil, is responsible for debris scavenging, complement-mediated opsonization of bacteria, and bacteria destruction via oxidative burst mechanisms (i.e., superoxide and hydrogen peroxide formation). The neutrophil kill bacteria and decontaminate the wound from foreign debris. (Sabiston et al., 2001)

The second stage of wound healing is the proliferative phase. Epithelialization, angiogenesis, granulation tissue formation, and collagen deposition are the principal steps in this anabolic portion of wound healing. Epithelialization occurs early in wound repair. If the basement membrane remains intact, the epithelial cells migrate upwards in the normal pattern. This is equivalent to a first-degree skin burn. The epithelial progenitor cells remain intact below the wound, and the normal layers of epidermis are restored in 2-3 days. If the basement membrane has been destroyed, similar to a second- or third-degree burn, then the wound is re-epithelialized from the normal cells in the periphery and from the skin appendages, if intact (hair follicles, sweat glands). (Folkman et al., 1992)

Angiogenesis, stimulated by TNF-alpha, is marked by endothelial cell migration and capillary formation. The new capillaries deliver nutrients to the wound and help maintain the granulation tissue bed. The migration of capillaries into the wound bed is critical for proper wound healing. The granulation phase and tissue deposition require nutrients supplied by the capillaries, and failure for this to occur results in a chronically unhealed wound. Mechanisms for modifying angiogenesis are under study and have significant potential to improve the healing process. (Sabiston et al., 2001)

The final part of the proliferative phase is granulation tissue formation. Fibroblasts differentiate and produce ground substance and then collagen. The ground substance is deposited into the wound bed; collagen is then deposited as the wound undergoes the final phase of repair. Many different cytokines are involved in the proliferative phase of wound repair. The steps and the exact mechanism of control have not been elucidated. Some of the cytokines include PDGF, insulin like growth factor, and EGF. All are necessary for collagen formation. The final phase of wound healing is the maturational phase. The wound undergoes contraction, ultimately resulting in a smaller amount of apparent scar tissue. The entire process is a dynamic continuum with an overlap of each phase and continued remodeling. The wound reaches maximal strength at one year, with a tensile strength that is 30% of normal skin. Collagen deposition continues for a prolonged period, but the net increase in collagen deposition plateaus after 21 days.

Collagen

Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals, making up about 40% of the total. It is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins such as enzymes. It is tough and inextensible, with great tensile strength, and is the main component of cartilage, ligaments, tendons, bone and teeth. Along with soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging. It strengthens blood vessels and plays a role in tissue development.

Collagen acts as a scaffolding for our bodies, controls cell shape, differentiation, broken bones regeneration; wounds heal and blood vessels growth to feed healing areas. The Collagen mesh provides the blueprint, the road map and the way. Collagen is the fibrous protein constituent of skin, cartilage, bone, and other connective tissue.

Collagen makes up 75% of our skin. Collagens are the primary fibers of animal extra cellular structure. They provide tensile strength and elasticity to the matrices supporting body cells. Three strands of repeating amino acids coil themselves, left-handed, into the unique collagen triple helix. Then these coils weave themselves right-handed into a cable, like small steel wires braided into the cables of a suspension bridge. In fact, collagen has a greater tensile strength than steel. Presumably, this complex structure has been devised by nature to be invulnerable to the circulating enzymes and other materials in the body. Nature accomplished this purpose superbly which is why no other enzyme but a "collagenase" can break it into its component parts.

When the body needs to build any new cellular structure as in the healing process, collagen and/or collagen fragments play a central role. Although the role of collagen as scaffolding has been known for some time, we now know that collagen controls cell shape and differentiation, migration, and the synthesis of a number of proteins. This is why broken bones regenerate and wounds heal, why blood vessels grow to feed healing areas. The collagen mesh provides the blueprint, the road map and the way.

Collagenase

Collagenase is a drug that breaks down collagen in damaged tissue and helps healthy tissue to grow. Application of collagenase to a wound may help it heal faster. You need to eat nutritious foods and care for your wound as directed by your health care professional. A generic collagenase ointment is available. Collagenase is an enzymatic debrider that cleans the wound of any dead tissue leaving the wound bed ready for healing.

Collagenases break down the native collagen that holds animal tissues together, are made by a variety of microorganisms and by many different animal cells. The most potent collagenase is the "crude" collagenase secreted by the anaerobic bacteria "Clostridium histolyticum". "Crude" collagenase refers to the fact that the material is actually a mixture of several different enzymes besides collagenase that act together to break down tissue. It is now known that two forms of the collagenase enzyme are present. With a few exceptions different commercial collagenase are all made from C. histolyticum, or is recombinant versions where, Escherichia coli expresses a gene cloned from C. histolyticum.

Collagenase ointment is a sterile enzymatic debriding ointment which contains 250 collagenase units per gram of white petrolatum USP. The enzyme collagenase is derived from the fermentation by "Clostridium histolyticum". It possesses the unique ability to digest collagen in necrotic tissue.

Drug Category: Anti-Ulcer Agents Topical

Indication: For treatment of chronic dermal ulcers and severe skin burns

Pharmacology: Used in the treatment of skin ulcers and sever burns, collagenase is able to digest collagen in necrotic tissue at physiological pH. Collagenase thus contributes towards the formation of granulation tissue and subsequent epithelization of dermal ulcers and severely burned areas.

Mechanism of Action

Collagenase is a protease that is specific to collagen. The triple helical region of interstitial collagens is highly resistant to most cell proteinases. However, during remodeling of the connective tissue in such processes as wound healing and metastasis, collagen becomes susceptible to cleavage by collagenases. Collagenase cleaves all 3 alpha helical chains of native Types I, II and III collagens at a single locus by hydrolyzing the peptide bond following the Gly residue of the sequence: Gly 775-(Ile or Leu) 776-(Ala or Leu) 777 located approximately three-fourths of the chain length from each N-terminus. The current management of decubitus ulcers, factors in wound healing and the role of enzymes in treatment are discussed. The therapeutic benefits of collagenase ointment in 21 patients are described, supplemented by serial color photographs. Statistical evidence is provided for the conclusion that collagenase ointment is an excellent adjunct to therapy. (Rao et al., 1975)

Materials and Methods

Drug bank

The Drugbank database is a unique bioinformatics and cheminformatics resource that combines detailed drug data (i.e. chemical, pharmacological and pharmaceutical) with comprehensive drug target information (i.e. sequence, structure, and pathway). The database contains nearly 4300 drug entries including >1,000 FDA-approved small molecule drugs, 113 FDA-approved biotech drugs (protein/peptide), 62 nutraceuticals and >3,000 experimental drugs. Additionally, more than 6,000 protein (i.e. drug target) sequences are linked to these drug entries. Each DrugCard entry contains more than 80 data fields with half of the information being devoted to drug/chemical data and the other half devoted to drug target or protein data. A drug database where the drugs for disease wound healing are known. From this database the mechanism of action of the drug to the disease is known and the target protein can also be known.

NCBI

The National Centre for Biotechnology Information established on November 4, 1988, as a division of the National Library of Medicine at the National Institutes of Health. NLM was chosen for its experience in creating and maintaining biomedical databases, and because as part of NIH, it could establish an intramural research program in computational molecular biology. The collective research components of NIH make up the largest biomedical research facility in the world.

As a national resource for molecular biology information, NCBI's mission is to develop new information technologies to aid in the understanding of fundamental molecular and genetic processes that control health and disease. More specifically, the NCBI has been charged with creating automated systems for storing and analyzing knowledge about molecular biology, biochemistry, and genetics; facilitating the use of such databases, software by the research and medical community; coordinating efforts to gather biotechnology information both nationally and internationally; performing research into advanced methods of computer-based information processing for analyzing the structure and function of biologically important molecules. NCBI contains a chemical database called PubChem compound. In NCBI the search is given in PubChem compound for the drug collagenase to get the chemical structure and the physical properties of the drug.

PubChem

PubChem is a database of chemical molecules. The system is maintained by the NCBI which belongs to the United States National Institutes of Health.

PubChem Compound: Search unique chemical structures using names, synonyms or keywords. Links to available biological property information are provided for each compound. It contains pure and characterized chemical compounds.

PDB

The RCSB PDB provides a variety of tools and resources for studying the structures of biological macromolecules and their relationships to sequence, function, and disease. The RCSB is a member of the wwPDB whose mission is to ensure that the PDB archive remains an international resource with uniform data. This site offers tools for browsing, searching, and reporting that utilize the data resulting from ongoing efforts to create a more consistent and comprehensive archive. Protein data bank which contains the 3D structure of the protein. The 3D structure of the target protein collagen (PDB ID-1Q7D) is downloaded from the PDB.

NCI

The National Cancer Institute of the NIH in Bethesda, U.S.A., has been collecting samples of chemical compounds within its Developmental Therapeutics Program for more than a decade. Nearly 250,000 structures have been received and a large portion of them screened for anti-tumor activity using standardized plated tumor cell cultures. Recently, an anti-viral screening program has been added to detect potential anti-viral (especially anti-AIDS) properties of these compounds. The DTP program offers free screening of the submitted samples while the contributors retain commercial rights for interesting compounds. However, the results for inactive structures or compounds which for other reasons do not possess commercial potential are published after a time period of about two years.

Researchers who prove an authentic interest can order samples of the stored submitted compounds for further experimentation. The registration of the compounds and their associated screening results was begun with a custom in-house data repository system. Recently, the tabular numeric data has been transferred to an Oracle database. However, there was no convenient method of access to the accumulated data outside the NIH, where a simple Telnet-based alphanumeric interface was available to the researchers. NCI, a database of ligands where the chemical structure of the drug collagenase is drawn in editor page and the data is transferred to query page. In the query page the search is given by drug name and start search is selected to go to hit list page. In the hit list page the five analogs were selected and retrieved in PDB format and they are taken as ligands.

HEX

Hex is an interactive molecular graphics program for calculating and displaying feasible docking modes of pairs of protein and DNA molecules. Hex can also calculate small-ligand/protein docking (provided the ligand is rigid), and it can superpose pairs of molecules using only knowledge of their 3D shapes.

The main thing which distinguishes Hex from other macromolecular docking programs and molecular graphics packages is its use of spherical polar Fourier correlations to accelerate the docking and superposition calculations. The graphical nature of Hex came about largely as the results of such docking calculations can be visualized in a natural and seamless way, without having to export unmanageably many (and usually quite big) coordinate files to one of the many existing molecular graphics packages. For this reason, the graphical capabilities in Hex are relatively primitive compared to commercial packages, although these days one can do quite a lot with a few calls to OpenGL. In Hex's docking calculations, each molecule is modelled using 3D parametric functions which are used to encode both surface shape and electrostatic charge and potential distributions. The parametric functions are based on expansions of real orthogonal spherical polar basis functions. Essentially, this allow each property to be represented by a vector of coefficients. Hex's surface shape representation uses a novel 3D surface skin model of protein topology, whereas the electrostatic model is derived from classical electrostatic theory. By writing an expression for the overlap of pairs of parametric functions, one can derive an expression for a docking score as a function of the six degrees of freedom in a rigid body docking search. With suitable scaling factors, this docking score can be interpreted as an interaction energy, which we seek to minimise. Due to the special orthogonality property of the basis functions, the correlation (or overlap as a function of translation/rotation operations) between a pair of 3D functions can be calculated using expressions which involve only the original expansion coefficients. In many respects, this approach is similar to conventional fast Fourier transform (FFT) docking methods which use a Cartesian grid to perform the Fourier transforms. However, the FFT approach only accelerates a docking search in three translational degrees of freedom whereas with a spherical polar approach, we can both translate and rotate the coefficient vectors to generate and evaluate candidate docking orientations in what is effectively a six dimensional Fourier correlation. Hex, a docking tool used to dock the receptor and ligand in order to find to which active site the ligand is bonded. Here the receptor is collagen protein and the ligands are 2,3-butanedione dioxime,1-bromo-2,5-pyrrolidinedione, 2-ethyl-1,2-diphenyl-1-butanol, 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one and 7-amino-4-methyl[1,8]naphthyridin-2-ol are docked and the docked complex is saved in PDB extension.

Swiss-PDB

Swiss-PDB Viewer is an application that provides a user friendly interface allowing to analyze several proteins at the same time. The proteins can be superimposed in order to deduce structural alignments and compare their active sites or any other relevant parts. Amino acid mutations, H-bonds, angles and distances between atoms can be obtained easily thanks to the intuitive graphic and menu interface. Moreover, Swiss-PDB Viewer is tightly linked to Swiss-Model, an automated homology modeling server developed within the Swiss Institute of Bioinformatics (SIB) in collaboration between Glaxo Smith Kline R&D and the Structural Bioinformatics Group at the Biozentrum in Basel.

Working with these two programs greatly reduces the amount of work necessary to generate models, as it is possible to thread a protein primary sequence onto a 3D template and get an immediate feedback of how well the threaded protein will be accepted by the reference structure before submitting a request to build missing loops and refine side chain packing. Swiss-PDB Viewer can also read electron density maps, and provides various tools to build into the density. In addition, various modeling tools are integrated and command files for popular energy minimization packages can be generated. Swiss-PDB Deep Viewer, a visualization tool where the docked complex is opened and color is given by chain in order to have the differentiation between receptor and ligand. The specific atoms in the ligand were selected and the groups are selected within 10 angstrom units. The groups that are present within the given angstrom units are displayed in red color in control panel which can be viewed from the window menu. The amino acids that are in red color are noted.

CAST P

In order to perform their functions, proteins interact with other molecules, including other proteins, ligands, substrates and DNA. The three dimensional shape of a protein is a key factor in these interactions, providing docking sites or blocking access to particular amino acids. Knowledge of protein surface structure enables detailed studies of the relationship of protein structure and function. Specifically, characterization of protein surface regions helps to analyze enzyme mechanism, to determine binding specificity and to plan mutation studies. It can also facilitate the identification of the biological roles for newly solved protein structures with an unknown function.

CAST P is a web server that aims to provide a detailed quantitative characterization of interior cavities and surface pockets of proteins, which are prominent concave regions of proteins that are frequently associated with binding events. In CAST P, cavities are defined as buried unfilled empty space inside proteins after removing all heterogenous atoms that are inaccessible to solvent molecules from outside. Pockets are defined as concave caverns with constrictions at the opening on the surface regions of proteins. Unlike cavities, pockets allow easy access for solvent molecules.

CAST P identifies all pockets and cavities on a protein structure and provides a detailed listing of all atoms participating in their formation. It also measures the volume and area of each pocket and cavity analytically, using both the solvent accessible surface and molecular surface models. In addition, it measures the size of mouth openings of individual pockets, which helps to assess the accessibility of binding sites to various ligands and substrates. CAST P, an active site prediction tool, in which the PDB-ID of the collagen is given and the search is selected. It shows the active sites present in the structure of collagen and the amino acids that are involved in the active sites. The amino acids which have got from the Swiss-PDB deep viewer is referred with these amino acids and the active site is known.

Results

Wound healing, or wound repair, is the body's natural process of regenerating dermal and epidermal tissue. When an individual is wounded, a set of events takes place in a predictable fashion to repair the damage. It noticed that the skin protein collagen was prevailing in wound, which forms the receptor protein for wound healing process. The 3D structure of receptor protein collagen (PDB ID-1Q7D) from PDB, it contains triple helical structure. (Fig: 1.a & 1.b). In the drug bank the search is given for wound healing to find the drugs that are used to treat the disease, nearly 13 drugs were available (Fig: 2, Table: 1). Collagenase is the drug which binds on the collagen receptor.

The chemical structure of the Collagenase drug is retrieved from the NCBI PubChem compound. (Fig: 3a-c) Collagenase has molecular weight of 426.509 g/mol, and 4 Hydrogen bond donor and 5 hydrogen bond acceptor. The chemical structure is then drawn in the NCI editor page (Fig: 4.a) and the data is transferred to query page. (Fig: 4.b). In the query page the search is given to get the hits of the drug compound collagenase which are called as ligands. (Fig: 4.c). It has given five hits with structure IDs 9,12,29,36 and 99. (Fig: 4.c.1-.5). These analogs are saved in the PDB-Extension in order to perform docking.

The matching and docking is done by using HEX-Tool (Fig: 5.a-d). The analogs which are collected from NCI and the collagen (receptor) is opened one by one docking is performed and where in PDB Extension. (Fig: 5.e) The Hex Message showed the clusters formed and maximum and minimum energy during docking process (Fig: 5.f). The maximum clusters are shown by the complex collagen and 2-ethyl-1, 2-diphenyl-1-butanol. Its maximum and minimum energy during docking process is found to be -225.58 and -257.79 respectively. 30 clusters formed during the docking process of the Collagen and 1-bromo-2,5-pyrrolidinedione, its maximum and minimum energy is found to be -182.34 and -223.21 respectively for the collagen and 5-methyl2-Phenyl-2,4-dihydro-3H-pyrazol-3-one. (Table: 2).

The docked complex is then opened in Swiss- PDB Deep Viewer (Fig: 6.a) and the color is selected by chain in order differentiate the triple helical structure of the collagen and the ligand. Then the ligand is selected and the search is given to find the interacting amino acids with the selected angstrom units. The interacting amino acid of Collagen receptor, when the analog of Collagenase drug is docked, was glycine, proline and hydroxyproline. In the case of docking complex like Collagen and 1-bromo-2, 5-pyrrolidinedione, Collagen and 5-methyl2-Phenyl-2,4-dihydro-3H-pyrazol-3-one, having the common interacting amino acids proline and hydroxyproline were present (Fig: 6.b); (Table: 3-7).

The CAST P is the active site analysis tool, the PDB-ID of the protein collagen is uploaded in the CAST P. The 3D structure of the protein is viewed along with its 2 binding pockets (Fig: 7.a & 7.b). This collagen protein contains only 2 binding pockets and the amino acids such as proline & hydroxyproline are present in these pockets.

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Discussion

Cutaneous wound healing is a self motivated physiological process of cell regeneration which occurs without any external stimuli. In general, dermal injury is accomplished by fibroplasia, angiogenesis and migration of fibroblast, endothelial cells and epithelial cells lead to wound contraction. Collagens are the primary fibers of animal extra cellular structure. They provide tensile strength and elasticity to the matrices supporting body cells. Collagen is a connective tissue protein having a triple-stranded helical structure and it plays an important role in many physiological processes like wound healing process by acting as a tissue scaffold. It is used as a carrier vehicle for cells in tissue engineered products and growth factors in dermal wound healing.

In the present study, the analogs of Collagenase drug had a positive role in the process of wound healing. The receptor protein collagen (PDB ID-1Q7D) 3D structure retrieved from PDB, it contains triple helical structure. In the drug bank the search is given for wound healing to find the drugs that are used to treat the disease. The chemical structure of the drug compound collagenase which acts on collagen is retrieved from the NCBI PubChem compound (DRUG ID-197672). The chemical is then drawn in the NCI editor page and the data is transferred to query page. In the query page the search is given to get the hits of the drug compound collagenase which are called as ligands. It has given five hits with structure IDs 9,12,29,36 and 99. These analogs were saved in the PDB extension in order to perform docking.

The tool HEX is used for docking. In the hex tool the collagen receptor is opened and the ligands which were collected from the NCI are opened one by one and performed docking. After docking is completed the docked complex is saved in PDB extension. The clusters formed during docking process, minimum and maximum energy in docking is noted from the hex messages

The docked complex is then opened in Swiss PDB Deep Viewer and the color is selected by chain in order differentiate the triple helical structure of the collagen and the ligand. Then the ligand is selected and the search is given to find the interacting amino acids with the selected angstrom units (10). The amino acids presented within the selected area can be noted from the control panel where those particular amino acids will be colored in red color.

The castP is the active site analysis tool, the PDB id of the protein collagen is uploaded in the Castp. The 3D structure of the protein is viewed along with its 2 binding pockets. This collagen protein contains only 2 binding pockets and the amino acids such as proline & hydroxyproline are present in these pockets. These amino acids are potentially active in triple helical structure of collagen receptor for collagenase ligand. Collagenase inhibits the active site of collagen to break the triple helical structure, to release fibrin. Fibrin prevents the blood loss in wound.

The analogs of collagenase drug acts on the amino acids such as proline and hydroxyproline to inhibit their role in the triple helical structure of collagen protein and to release fibrin or fibronectin which prevents blood loss in wound.

It is finally concluded that in the five analogs of collagenase drug the most effective analogs which are acting on the Proline-6 and Hydroxyproline -7 are responsible for forming the triple helical structure of the collagen protein. It can be cleaved by the action of three analogs like 1-bromo-2,5-pyrrolidinedione, 2-ethyl-1,2-diphenyl-1-butanol and 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one.

References

[1] Clark R A F 1985 Cutaneous tissue repair: Basic biologic considerations; J Am Acad Dermatol. 13 701-725.

[2] Cohen I K, Diegelmann R F and Lindblad W J 1992 Wound Healing: Biochemical and Clinical Aspects. Philadelphia, Pa: WB Saunders.

[3] Folkman J and Shing Y 1992 Angiogenesis; J Biol Chem. 267(16) 10931-4.

[4] Goepel J R 1996 Responses to cell injury. General and Systematic Pathology, Ed. Underwood, J.C.E, Second edition, Churchil Livingstone, London, UK 121-122.

[5] Matsuda H K, Sato H, Sawada J, Itakura A, Fanaka A, Matsumoto M, Konno K, Ushio H and Matsuda K 1998 Role of nerve growth factor in cutaneous wound healing accelerating effects in normal and healing-impaired diabetic mice; J. Expression Medical 187 297-306.

[6] Micera A, Vigneti E, Pickholtz D, Rerch R, Pappo Q, Bonini S, Magaart F X, Aloe L and Levi-Schaffer F 2001 Nerve growth factor displays stimulatory effects on human skin and lung fibroblasts, demonstrating a direct role for this factor in tissue repair; Proc. Natl. Acad. Sci. 98 (11) 6162-6167.

[7] Rao D B, Sane P G and Georgiev E L 1975 The Effects of Santyl and Infection on Burn Healing in Swine; J. Am. Geriatrics Soc. 23 22

[8] Sabiston D C, Townsend C M and Beauchamp D R, 2001 eds: Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 16th ed. Philadelphia, Pa: WB Saunders.

G. Dharmaraj (1) and S. Arumugam (2) *

(1) Department of Biotechnology, Nandha Arts & Science College, Erode-52

(2) Department of Plant Biology & Biotechnology Govrnment Thirumagal Mills College, Gudiyattam, Vellore Dist, India-632602

* Corresponding author E-mail: arumugams@rediffmail.com
Table 1: The list of drugs that are used to cure wound healing
along with their Accession number, Generic name and Chemical
formula which is from Drug bank.

Accession No Generic Name Chemical Formula

APRD00674 Dexamethasone C22H29FO5
APRD01019 Hydrocortisone C21H30O5
BIOD00010 Collagenase C5028H7666N1300O1564S21
EXPT00124 dihydrogenphosphate ion H2O4P11-
EXPT00922 citric acid C6H8O7
EXPT01726 heme C34H32N4O4FE1
EXPT01729 1,3-dedimethyl-1,3-divinyl C36H32N4O4Fe1
 heme
EXPT01785 histamine C5H9N3
EXPT01865 imidazole C3H5N21+
EXPT02726 4-iodopyrazole C3H3N2I1
 (3r)-3-{[(benzyloxy)carbonyl]
EXPT03288 amino}-2-oxo-4-phenylbutane- C18H18N3O3
 1-
 diazonium
NUTR00014 L-Arginine C6H14N4O2
NUTR00033 L-Leucine C6H13NO2

Table 2: The number of clusters formed and the minimum and maximum
energy used during docking.

DOCKING COMPLEX CLUSTERS E MAX E MIN

Collagen & 1-bromo-2,5- 30 -69.90 -87.25
 pyrrolidinedione
Collagen & 2,3-butanedione 14 -157.71 -189.43
 dioxime
Collagen & 2-ethyl-1,2- 87 -225.58 -257.79
 diphenyl-1-butanol
Collagen & 5-methyl-2- 16 -182.34 -223.21
 phenyl-2,4-dihydro-3H-
 pyrazol-3-one
Collagen & 7-amino-4- 20 -173.81 -213.23
 methyl[1,8]naphthyridin-
 2-ol

Table 3: The interacting amino acids in the collagen receptor
when the analog 1-bromo-2,5-pyrrolidinedione of collagenase
drug is docked.

DOCKING COMPLEX CHAIN INTERACTIN
 G AMINO
 ACIDS

Collagen & 1-bromo-2,5- A GLY 5
 pyrrolidinedione PRO6
 HYP 7
 GLY 8
 PHE 9
 HYP 10
 GLY 11
 B GLY 5
 PRO 6
 HYP 7
 GLY 8
 PHE 9
 HYP 10
 GLY 11
 C HYP 4
 GLY 5
 PRO 6
 HYP 7
 GLY 8
 PHE 9

Table 4: The interacting amino acids in the collagen receptor
when the analog 2,3-butanedione dioxime of collagenase drug
is docked.

DOCKING COMPLEX CHAIN INTERACTING
 AMINO ACIDS

Collagen & 2,3-butanedione dioxime A GLY 17
 PRO 18
 HYP 19
 GLY 20
 PRO 21
 HYP 22
 B GLY 17
 PRO 18
 HYP 19
 GLY 20
 PRO 21
 C PRO 15
 HYP 16
 GLY 17
 PRO 18
 HYP 19
 GLY 20

Table 5: The interacting amino acids in the collagen receptor
when the analog 2-ethyl-1,2-diphenyl-1-butanol of collagenase
drug is docked.

DOCKING COMPLEX CHAIN INTERACTIN
 G AMINO
 ACIDS

Collagen & 2-ethyl-1,2-diphenyl-1- A GLY 2
 butanol PRO 3
 HYP 4
 GLY 5
 PRO 6
 HYP 7
 GLY 8
 B GLY 2
 PRO 3
 HYP 4
 GLY 5
 PRO 6
 HYP 7
 GLY 8
 C GLY 2
 PRO 3
 HYP 4
 GLY 5
 PRO 6

Table 6: The interacting amino acids in the collagen receptor
when the analog 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one of
collagenase drug is docked.

DOCKING COMPLEX CHAIN INTERACTI
 NG AMINO
 ACIDS

Collagen & 5-methyl-2-phenyl-2,4- A GLY 5
 dihydro-3H-pyrazol-3-one PRO 6
 HYP 7
 GLY 8
 PHE 9
 B GLY 2
 PRO 3
 HYP 4
 GLY 5
 PRO 6
 HYP 7
 C GLY 2
 PRO 3
 HYP 4
 GLY 5
 PRO 6
 HYP 7

Table 7: The interacting amino acids in the collagen receptor
when the analog 7-amino-4-methyl[1,8]naphthyridin-2-ol of
collagenase drug is docked.

DOCKING COMPLEX CHAIN INTERACTI
 NG AMINO
 ACIDS

Collagen & 7-amino-4- A HYP 16
 methyl[1,8]naphthyridin-2-ol GLY 17
 PRO 18
 HYP 19
 GLY 20
 B PRO 15
 HYP 16
 GLY 17
 PRO 18
 HYP 19
 GLY 20
 C PRO 15
 HYP 16
 GLY 17
 PRO 18
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Author:Dharmaraj, G.; Arumugam, S.
Publication:International Journal of Biotechnology & Biochemistry
Article Type:Report
Date:May 1, 2010
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