Significance of Molecular Surfaces and Different Visualization Tools in Drug Designing: A Review

Significance of Molecular Surfaces and Different Visualization Tools in Drug Designing: A Review

Om Silakari (Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India), Himanshu Verma (Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India) and Shalki Choudhary (Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India)
DOI: 10.4018/IJQSPR.2019070101
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Molecular surfaces have comprehensive utility in the field of drug discovery. A deeper insight into different aspects of molecular surfaces is essential for the researchers to successfully identify a lead molecule with excellent pharmacokinetic profile. Therefore, the concept of molecular surfaces cannot be overlooked when designing a novel molecule. This is a better approach to correlate molecular surfaces with binding interaction, binding affinity, and their orientation, which in turn might produce information about the probable pharmacological potential. A profound knowledge of surface properties may provide more selective drugs in return, especially for the treatment of diseases where selectivity is the major issue associated with pathological conditions. This review sheds light on the various types of molecular surfaces, different visualization tools and their application in rationale drug designing. Moreover, this report also discloses the forthcoming perspectives of molecular surfaces that may create new ideas to deal with drug selectivity issues.
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1. Introduction

Dealing with a new drug molecule is not an easy task, if we only have information about the types and arrangement of the atoms in that particular molecule. Understanding the spherical representation or the space filled three-dimensional model of molecular structure along with their valence geometry has become important in the drug design process (Connolly, 1983b). This type of three-dimensional model of any molecule represents the molecular surface (MS) which is basically any surface that surrounds nuclei of the molecules (Spackman & Jayatilaka, 2009). In these 3D models, instead of the nature of atoms and types of bond in-between, the surface of atoms is the focal point. The earliest definition of the MS has been published by Lee and Richards in 1971where they termed it as accessible surface area. According to them, “Accessible surface area, A, of an atom is the area on the surface of a sphere of radius R, at each point of which the center of a solvent molecule can be placed in contact with this atom without penetrating any other atoms of the molecule” where R is the sum of van der Waal’s radius of atom or chosen radius of solvent molecule (Lee & Richards, 1971). In terms of quantum mechanics, it is not precisely recognized as surface, but the electronic distribution around the nuclei and is regarded as a 3D molecular body whose boundary is the molecular surface (Todeschini & Consonni, 2009). The researchers also reported a method which distinguishes the surface atom from buried atoms and regarded total molecular surface as the sum of atomic surfaces. Thus, on the basis of reported facts it can be concluded that MS is an interface through which mutual interaction of molecules takes place (Peitsch, 2008). There are three major molecular surfaces that have been put forward such as van der Waals surface (VWS), solvent accessible surface (SAS) and solvent excluded surface (SES), Partial surfaces (hydrophilic and hydrophobic). Among these surfaces, VdW surface and SAS are both topological boundaries formed by union of spheres, whose geometric features are easier to understand, while understanding SES is quite complicated. The surfaces formed by topological boundaries have strong correlation with some topological indices such as Wiener number, Z value, branching index (Amidon & Anik, 1976). These indices were put forward by Schultz for the first time in 1989 (Schultz, 1989). It is reported that the Schultz molecular topological index decrease with increase in the branching of carbon skeleton (Gutman, 1994). Initially, it was Lee and Richard, who gave the concept of SAS and SES. Later, numerous advancements were made to have a more reliable MS representation system (Figure 1) (Quan & Stamm, 2017). Further, Greer and Bush in year 1978 transformed the theoretical concept of MS into computer graphics which helped in perceiving the better picture of these surfaces (Greer & Bush, 1978). About five years later, an advanced algorithm was introduced by Connolly for computing the MS in which a hypothetical probe was placed over the atom of the molecule and the point where this probe touches the atom was considered as MS (Connolly, 1983a). With time, the Connolly’s algorithm was ruled over by some analytical techniques for the representation of molecular surface. The analytical representation technique is based on the spherical harmonic functional description applied over pre-computed surface (Duncan & Olson, 1995; Klein et al., 1990; Sanner, Olson, & Spehner, 1995; Voorintholt, Kosters, Vegter, Vriend, & Hol, 1989). The algorithm of analytical molecular surface is useful in molecular docking studies and computing the intermolecular surface interactions (D. T. Stanton & Jurs, 1990). The analytical molecular surface technique also uses sophisticated computer graphics display algorithms for smooth representation of surfaces (Connolly, 1983a). Understanding the geometric/topological properties of molecules may be significantly applicable in molecular docking study by identifying cavities and combined surface-based and volume-based information. Moreover, surface properties are well correlated to the applied force-field (OPLS, Amber, CHARMM etc.), as thermal vibrations of the atom determines the rapid changes on the surface. Thereby, sound knowledge of force-fields and molecular surface properties can help in understanding the spatial organization of the atoms, enough to determine the biomolecular properties of the molecules (Rocchia & Spagnuolo, 2014). MS has its application in the field of chemistry, biochemistry, physics and biomedicine (Quan & Stamm, 2017). Additionally, it can be well explored to study enzymology, drug designing and the elucidation of molecular diseases such as sickle cell anemia, location of possible antigenic determinants on viruses and location of specific DNA base sequences by proteins and drugs (Connolly, 1983b). This report is a brief summary of different molecular surfaces which exhaustively describes the key points of mainly three molecular surfaces which play a crucial role in drug designing. The thorough understanding of these surfaces may assist the medicinal chemists to design more potent molecules with higher selectivity.

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