Question

Q1.

(a) What should molecular properties of a small molecule drug be such that its ADME parameters
transports it efficiently across the blood brain barrier? Give examples of the drugs that have these
structural properties (e.g. active transporters)

(b) Use principles of molecular modeling and drug
design to explain the mechanisms of how enzymes evolve new functions.

(c) How is the Buckingham
potential a more realistic one compared to the Lennard Jones potential in modeling VDW interactions
in proteins and nucleic acids? Write out the potential energy expression using the Buckingham
potential. Define and explain its adjustable parameters.

(d) How would you combine a MC and a MD
algorithm to perform a molecular simulation on a biological system.

Q2.

(a) What are the differences between an energy based ligand design method such as GRID and a
knowledge based one like LUDI? What are the requirements of a knowledge based ligand design
method?

(b) Interpret the following QSAR equation: log (1/C)=k 1 ?-k 2 ? 2 + k 3 ?. How are factorial design
methods using in QSAR compound selection? Briefly outline how multiple linear regression analysis is
used in the derivation of a QSAR equation. How is cross-validation used for checking the quality of a
regression based QSAR model?

Q3.

(a) Use the example of molecular docking of the antibiotic netropsin to DNA to distinguish
quantitatively the differences between steepest descent and conjugate gradient methods for initial
refinement and stringent minimization. What qualitative conclusions can be drawn about the efficacy
of these two minimization techniques with respect to this docking experiment?

(b) Using two
examples, explain the thermodynamic differences between the Molecular Dynamics and Monte Carlo
methods. What are the advantages to choosing periodic boundary conditions in ANY molecular
simulation of a macromolecule? Use a diagram to plot 4 such periodic cell shapes. What important
class of applied molecular simulations have benefitted from the usage of periodic boundary
conditions?

Answer 1

Ans a. In order for the drug to be transported across the blood brain barrier, it need to be highly lipophilic and should posses the partion coefficient value of lipid to water more than one. Drugs acting on CNS are the ones which posses the ability to cross the blood brain barrier. Some of those are the phenytoin drug possesing hydantoin central ring, carbamazepine having an iminostilbene ring. The active transportation of such molecules occur by the transport by p glycoprotein.

Ans b. Molecular modelling and drug design provides a substantial degree of accuracy for the conformation of small molecule ligands within the appropriate binding site. Molecular modelling studies the lligand binding modes and the corresponding intermolecular interactions which which stabilize the ligand receptor complex. Hence it can be used in studying the bindinf of enzyme to substrate and thus imparting the activity.

Ans c. The alignment of Buckingham potential to the lennard jones potential reduces the abruptness in the energy potential curve study for the van der waals energy description. The imposition of Buckingham potential induces a good agreement for the interatomic compression whereas the lennard jones potential enables good agreement for large interatomic separatyion.

Ans d. Numerous approaches has been outlined for the MC MD combination. Someof them are:

1) Mixed MD/MC alogirithms where some atoms are moved by the MD and some by MC.

2) Hybrid MD/MC where alogarithms itself is a combination of MD and MC.

3) Sequential alogarithms where MD and MC cycles alternate.