some examples of the commercial programs, and Macromodel [4], Grasp [5], and
PyMOL [6] are some of the academic programs available. In all the stages, the
macromolecular design process depends heavily on the molecular structure and
visualizing it. X-ray structures of macromolecular targets/their inhibitor complexes
make it simple to visualize the active site of the enzyme, etc., where water coordination having hydrogen bonds with the backbone of amino acids can be seen.
During the design process, the active site water molecule can be replaced by the
suitable inhibitor which can bind with the catalytic residues. The above type of
molecular visualization was carried out with HIV-1 protease, and the crystallographic study of its complex confirmed this. There are many examples in the
literature like the above case using which inhibitors resulting as drugs have come
out. Molecular hydrophobicity maps are useful to understand the binding mechanism of inhibitors to the active site. Free energy perturbation calculations are used
in the above.
Lipinski’s “rule of five” is employed in the selection and filtering of compounds
with enhanced oral administration property. Four parameters are used as yardsticks,
such as hydrogen bond donors less than or equal to 5, hydrogen bond acceptors less
than or equal to 10, molecular weight should be under 500, and CLogP less than 5.
The lead molecules are tested for absorption (A), distribution (D), metabolism (M),
excretion (E), and toxicity (T) profile, also known as ADMET properties. These
physical and chemical properties have a greater influence on the biological effect of
the lead molecule, which determines how drug molecules can sustain in plasma and
can determine concentration for oral administration, and also indicates its effects.
In the discovery or in the refinement of new leads, thousands of compounds from
various databases are docked with the known target structures. During the docking,
the energies of the above complexes are evaluated and the one with the lowest
energy is selected as the possible lead compound. Many reviews deal with docking
approach [7–11]. During the initial calculation of docking, hundreds of inhibitors
may sometime be used. In this situation, receptor site is kept rigid and flexibility is
provided with the ligand. This is called rigid docking. After the analysis of score
and binding energy, few ligands will be selected for docking and now flexibility
will be given to both the receptor site and ligand for a better fit at the active site.
This is called induced fit docking (IFD). In this way, docking analysis can lead to
the selection of ligands in short time. There are many ligand databases available.
The binding constant of the compounds is related to the free energy of the
binding. Many computational tools provide rapid estimates of these free energy
changes. For very simple solutes, above calculations are possible using molecular
dynamics or Monte Carlo simulations [12]. Direct calculation of free energies of
binding is not possible for solutes of complex nature. In this situation, an indirect
way of calculating relative free energies of binding is possible [13]. In recent years,
computational alchemy methods have been applied to modify the binding of the
compounds. For increasing the solubility (and bioavailability), an aromatic H is
usually modified by OH and NH 2 . For enzymes like thymidylate synthase [14],
acetylcholinesterase [15], adenosine deaminase [16], and elastase [17], sets of
related inhibitors have been designed in the above way.
272
D. Velmurugan et al.
PyMOL [6] are some of the academic programs available. In all the stages, the
macromolecular design process depends heavily on the molecular structure and
visualizing it. X-ray structures of macromolecular targets/their inhibitor complexes
make it simple to visualize the active site of the enzyme, etc., where water coordination having hydrogen bonds with the backbone of amino acids can be seen.
During the design process, the active site water molecule can be replaced by the
suitable inhibitor which can bind with the catalytic residues. The above type of
molecular visualization was carried out with HIV-1 protease, and the crystallographic study of its complex confirmed this. There are many examples in the
literature like the above case using which inhibitors resulting as drugs have come
out. Molecular hydrophobicity maps are useful to understand the binding mechanism of inhibitors to the active site. Free energy perturbation calculations are used
in the above.
Lipinski’s “rule of five” is employed in the selection and filtering of compounds
with enhanced oral administration property. Four parameters are used as yardsticks,
such as hydrogen bond donors less than or equal to 5, hydrogen bond acceptors less
than or equal to 10, molecular weight should be under 500, and CLogP less than 5.
The lead molecules are tested for absorption (A), distribution (D), metabolism (M),
excretion (E), and toxicity (T) profile, also known as ADMET properties. These
physical and chemical properties have a greater influence on the biological effect of
the lead molecule, which determines how drug molecules can sustain in plasma and
can determine concentration for oral administration, and also indicates its effects.
In the discovery or in the refinement of new leads, thousands of compounds from
various databases are docked with the known target structures. During the docking,
the energies of the above complexes are evaluated and the one with the lowest
energy is selected as the possible lead compound. Many reviews deal with docking
approach [7–11]. During the initial calculation of docking, hundreds of inhibitors
may sometime be used. In this situation, receptor site is kept rigid and flexibility is
provided with the ligand. This is called rigid docking. After the analysis of score
and binding energy, few ligands will be selected for docking and now flexibility
will be given to both the receptor site and ligand for a better fit at the active site.
This is called induced fit docking (IFD). In this way, docking analysis can lead to
the selection of ligands in short time. There are many ligand databases available.
The binding constant of the compounds is related to the free energy of the
binding. Many computational tools provide rapid estimates of these free energy
changes. For very simple solutes, above calculations are possible using molecular
dynamics or Monte Carlo simulations [12]. Direct calculation of free energies of
binding is not possible for solutes of complex nature. In this situation, an indirect
way of calculating relative free energies of binding is possible [13]. In recent years,
computational alchemy methods have been applied to modify the binding of the
compounds. For increasing the solubility (and bioavailability), an aromatic H is
usually modified by OH and NH 2 . For enzymes like thymidylate synthase [14],
acetylcholinesterase [15], adenosine deaminase [16], and elastase [17], sets of
related inhibitors have been designed in the above way.
272
D. Velmurugan et al.