1. Introduction

The rapid development of high-performance computing intensifies the competition to invent faster supercomputers which invention is considered as a national pride. High-performance computing machines are highly valued for having adequate ability to solve complex problems related to national interests in several

sectors including national defense, energy, financial sectors and science. Within the global economic growth competition and the advancement in science and technology including the advancement in biology, chemistry, pharmacy and medicine, supercomputers play key roles. In-silico analysis has been developed as the computational approach [1, 2].

rearrangements obtained from molecular dynamic show novel-targetable areas. However, predicting the priori is still considered difficult, especially when a molecular dynamic conformation outperforms a virtual screening against the crystal

Virtual Screening of Sesquiterpenoid Pogostemon herba as Predicted Cyclooxygenase Inhibitor

This study evaluated whether molecular dynamic conformations lead to better virtual screening performance for nine ligand sesquiterpenoid/sesquiterpenoid Pogostemon herba to protein cyclooxygenase (COX-1/COX-2). The results of in silico analysis data will be completed with IC50 value determination and in-vitro and in-

Within the process of living system, protein-ligand interactions have been known to play central roles. It has been considered interesting to obtain more comprehensive understanding of protein interactions with small molecules because it leads to better understanding of various functions and therapeutic intervention. As a matter of fact, molecular recognition is a complex interplay of several factors including inter-molecular interactions of protein, ligand and the surrounding solvent, conformational variations of binding partners and the thermodynamics of molecular association. The non-covalent reversible binding of small-molecules to proteins also plays a central role in the field of biology. Several processes are known crucial in living systems that involve specific recognition of small molecule ligands by proteins. For instance, certain enzymes affect their substrates and catalyze chemical reactions inside the cells, where transporters recognize specific molecules based on the movement across membrane barriers, receptors that are specifically bind to hormones or other chemical messengers for inter- and intracellular communication. Finally, antibodies uniquely can bind to other chemical agents to mount vital defense mechanisms against infections and diseases. In general, protein-ligand binding in an aqueous environment is

A change in the free energy (ΔG) is always followed by chemical reactions and change in two other important quantities; enthalpy (ΔH)—the heat content and entropy (ΔS) that showed disorder of temperature-independent degree. The rela-

Some factors including electrostatic and van der Waals interactions, ionization effects, conformational changes and the role of solvent affect the changes in the binding of free energy. Those factors are manifested as either favorable or unfavorable changes in entropy and enthalpy. In order to create a spontaneous reaction, the free energy change should be negative at equilibrium, ΔG° which relates to the

where R is the gas constant and T is the absolute temperature. Using this relationship, free energy changes can be derived from experimentally measurable quantity, K. Biological K values exhibit a wide range from weak to very strong binding.

➔Protein � Ligand PL ð Þð Þ aq (1)

<sup>Δ</sup>G° <sup>¼</sup> <sup>Δ</sup>H–TΔ<sup>S</sup> (2)

<sup>Δ</sup>G° ¼ �RTlnK (3)

structure.

described as follows.

43

vivo evaluation of the biological activity.

DOI: http://dx.doi.org/10.5772/intechopen.85319

2. Theory of docking and virtual molecular dynamic

Protein Pð Þð Þ aq <sup>þ</sup> Ligand Lð Þð Þ aq

tionship between these quantities is shown as follows:

equilibrium constant (K) in this following expression:

Molecular interactions including protein-nucleic acid, drug-protein, proteinprotein, enzyme-substrate, and drug-nucleic acid play important roles in many essential biological processes, such as enzyme inhibition, signal transduction, antibody-antigen recognition, transport, gene expression control, cell regulation, up to multi-domain proteins assembly. Stable protein-protein or protein-ligand complexes are often produced by the interaction which complexes are considered essential in performing their biological functions. To determine the binding mode and affinity between interacting molecules, tertiary structure of proteins should be first identified. Unfortunately, conducting experiments to obtain complex structures has been considered challenging and expensive because the experiments would require X-ray crystallography or NMR. Docking computation has been considered a feasible and important approach to comprehend the protein–protein or protein-ligand interactions [3]. Experimental technique has been frequently used to determine the three-dimensional protein structures—and structure of the databases such as Protein Data Bank (PDB) and Worldwide Protein Data Bank. A total of 88,000 protein structures have been identified and most of them are significant in critical metabolic pathways which might be regarded as potential therapeutic target. Therefore, specific databases that contain binary complexes structures would be available, along with information about binding affinities, such as in PDBBIND, PLD, AffinDB and BindDB, molecular docking procedures improvement [3, 4].

In silico virtual screening is a popular identification technique used in in drug discovery projects which distinguishes true actives from inactive or decoy molecules effectively. To have better comprehension on the dynamic behavior of protein drug targets, compound databases can be screened against an ensemble of protein conformations through experiments or generated-computation [5]. Screening states include ligand preparation, protein targets, molecular docking, visualization, binding energy calculation, and scoring [6]. A computer simulation procedure in the form of molecular docking is commonly used to predict the conformation of certain receptor-ligand complex, which receptor is usually a protein or a nucleic acid molecule or the ligands in the form of a small molecule or other protein, or sesquiterpenoid/sesquiterpenoid alcohol interaction to protein cyclooxygenase, as shown Figure 1. In modern structure-based drug design, accurate prediction is necessary to determine the binding modes between the ligand and protein. Virtual screening is the most popular docking application that selects molecules from an existing database for further research. As the demand on this computational method keeps increasing, people expected a fast and reliable method. Another application used in this study was molecular complexes investigation [3, 6–11]. Previous studies have shown that dynamic molecular-generated conformations play considerable role in the identification of novel hit compounds because structural

Figure 1. Molecular docking-Molecular dynamic ligand to protein.

Virtual Screening of Sesquiterpenoid Pogostemon herba as Predicted Cyclooxygenase Inhibitor DOI: http://dx.doi.org/10.5772/intechopen.85319

rearrangements obtained from molecular dynamic show novel-targetable areas. However, predicting the priori is still considered difficult, especially when a molecular dynamic conformation outperforms a virtual screening against the crystal structure.

This study evaluated whether molecular dynamic conformations lead to better virtual screening performance for nine ligand sesquiterpenoid/sesquiterpenoid Pogostemon herba to protein cyclooxygenase (COX-1/COX-2). The results of in silico analysis data will be completed with IC50 value determination and in-vitro and invivo evaluation of the biological activity.
