THE UNIVERSITY OF LAHORE,

SARGODHA CAMPUS
B.Sc. (Hons) Chemistry

SUBMITTED BY:

SHAHZAD KHAN

REG. NO. :

BSCSR07191003

SUBMITTED TO:

DR SAMI ULLAH

TOPIC:

Importance of STEREOCHEMISTRY in COMPUTATIONAL ANALYSIS:

DATED:

03/06/2021

COURSE TITLE:

COMPUTATIONAL CHEMISTRY

SEMESTER:

BS 5TH
Importance of STEREOCHEMISTRY in
COMPUTATIONAL ANALYSIS:
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of
atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses
on stereoisomers, which by definition have the same molecular formula and sequence of bonded atoms
(constitution), but differ in the three-dimensional orientations of their atoms in space. For this reason, it is
also known as 3D chemistry—the prefix "stereo-" means "three-dimensionality"

An important branch of stereochemistry is the study of chiral molecules. Stereochemistry spans the entire
spectrum of organic, inorganic, biological, physical and especially supramolecular chemistry.
Stereochemistry includes methods for determining and describing these relationships; the effect on the
physical or biological properties these relationships impart upon the molecules in question, and the
manner in which these relationships influence the reactivity of the molecules in question (dynamic
stereochemistry).

ROLE OF STEREOCHEMISTRY IN COMPUTATIONAL

ANALYSIS:
Consideration of stereochemistry early in the identification and optimization of lead compounds can
improve the efficiency and efficacy of the drug discovery process and reduce the time spent on
subsequent drug development. These improvements can result by focusing on specific enantiomers that
have the desired potential therapeutic effect (eutomers), while removing from consideration enantiomers
that may have no, or even undesirable, effects (distomers).

A virtual screening campaign that correctly takes stereochemical information into account can, in theory,
be utilized to provide information about the relative binding affinities of enantiomers. Thus, the proper
enumeration of the relevant stereoisomers in general, and enantiomeric pairs in particular, of chiral
compounds is crucial if one is to use virtual screening as an effective drug discovery tool. As is obvious,
in cases where no stereochemical information is provided for chiral compounds in a 2D chemical
database, then each possible stereoisomer should be generated for construction of the subsequent 3D
database to be used for virtual screening.

However, acute problems can arise in 3D database construction when relative stereochemistry is encoded
in a 2D database for a chiral compound containing multiple stereogenic atoms but absolute
stereochemistry is not implied. In this case, we report that generation of enantiomeric pairs is imperative
in database development if one is to obtain accurate docking results. A study is described on the impact of
the neglect of enantiomeric pairs on virtual screening using the human homolog of murine double minute
2 (MDM2) protein, the product of a proto-oncogene, as the target.

Docking in MDM2 with GLIDE 4.0 was performed using the NCI Diversity Set 3D database and, for
comparison, a set of enantiomers we created corresponding to mirror image structures of the single
enantiomers of chiral compounds present in the NCI Diversity Set. Our results demonstrate that potential
lead candidates may be overlooked when databases contain 3D structures representing only a single
enantiomer of racemic chiral compounds.

Computational Chemistry for Drug Discovery

Computational chemistry uses physics-based algorithms and computers to simulate chemical events and
calculate chemical properties of atoms and molecules. In drug design and discovery, diverse
computational chemistry approaches are used to calculate and predict events, such as the drug binding to
its target and the chemical properties for designing potential new drugs.

Computational methods are nowadays routinely used to accelerate the long and costly drug discovery
process. Typically, once the drug discovery target is selected, drug discovery activities are divided into
those for (1) the hit identification phase, in which the aim is the identification of chemical compounds
with a promising activity toward the target; (2) the lead generation phase, in which hit compounds are
improved in potency against the target; and, finally, (3) the lead optimizationphase, in which lead
compounds are optimized