VIRTUAL SCREENING: THE PATH FORWARED
K.Phani Kumar* G.Sai Rajesh (Dept of Pharmacology)
G.Pulla Reddy College of Pharmacy, Hyderabad-028
Drug development includes various stages starting with identification of
the targets which is done by studying the sequence of gene(genomics)
and proteins (proteomics) after identifying the specific receptors drug
discovery process starts , in previous years many methods were used
like in .70’s animal experiments and isolated organs where used.90’s
drug discovery process includes molecular modeling and invitro
modeling techniques while in 20th century as technology developed
more and more methods emerged like combinatorial chemistry, gene
technology, high-throughput test models but the bottom line of this to
concentrate on ADME patterns. However, the percentage of conversion
of this molecule into drug like compounds is very less (0.0001%)
because this methods have immense drawback of not obeying lip’s kin
rule of five which is important for drug molecule to bind to the receptor,
virtual screening outweighs all these drawbacks and the percentage of
molecules turning out to be drug-like compounds is about 0.38% which
is very high compared to the previous techniques.
Virtual screening is the method of scanning of the database of
compound to identify the molecule of bioactivity of our interest, this
technique is in no way different from the real process of screening i.e.
both uses similar strategies for screening like 1)real screening uses the
bio-assay as the major for identifying the targets while it’s the
methodology in virtual screening for identifying the targets 2) in case of
real screening compound collections is restricted to those compound
which are physically available and it has many logistics and quality
issues, difficult to maintain where as in virtual screening collection not
only includes those whish are physically available but extended to those
which are not physically available but has potential ability to
synthesize ,it is easy to set up maintain and have no quality issues 3) in
virtual screening ranking is done based on scoring vs function where as
in real screening it is the one-point measurement used for determining
the ranking ,generally this method of determining is not effective
because it uses response obtained at particular concentration 4)finally
virtual screening uses protein and molecular modelling techniques for
structural information and real screening uses protein±ligand
complex ,X-ray crystallography for structural information. Due to these
similarities in screening of the compounds it completely replaces the
real screening and it is found that by using the virtual screening it
reduces the economy and labor.
Methodologies includes 1D fitting, 2Dfitting and 3Dpharmacophore
method
1Dfitting includes identification of the binary finger prints of the molecule,
2Dfitting defines the topography and molecular structure. Generally
1Dand 2d fitting combinations are used, it is traditional method in which
first identification of binary finger prints of the molecule is done then
comparing them with the standard compounds to define the molecular
structure. After obtaining the structure, similarity studies and similarities
vs activity is done, if the molecule is found to be active then molecule
shape signature is done for further proceedings.
3Dfitting it is most widely used and up coming technology it is done by
two methods
1) Ligand-based methods where it uses natural mediators as the lead
molecules, but the probability of conversion of these molecules into drug
like molecule is less due to fact that the compounds obtained by this
method found to have high molecular weight, highly polar, highly ionized
and too conformationly flexible .for increasing the probability, these lead
compounds are made Insilco and some attributes are changed in
computational techniques like
Physicochemical attributes eg:cimitidine and ranitidine from
histamine by replacement of primary ammonium group by nonbasic dipolar h-bond donor
Removal of unnecessary functionality eg: removal of polar
hydroxyl groups (OH) from guanosine results in potentially anti
herpus drug acyclovir
Removal of metabolically liable group like in case of sumaltriptin
which is an anti migraine obtained by replacing oxygen by sulphur
in 5HT (bioisosteric groups)
Conformational constrains are also given importance like in
cyclization of dopamine results in 7-OH DPAT
Apart from this there are many examples like β- blocker isoprotenol from
norepinephrine, ondansetron from 5HT etc
2)Pharmacophore or receptor method the main aim of this method is to
define a pharmacological model which defines the necessary futures of
molecule to be active on the target for this it require the compounds
which are structurally diverse and has varied degree of affinity toward
the target main purpose of this is to define minimum energy
conformation and spatial positions for molecule to be stable, then the
test molecule is overlaid Insilco and the best possible conformation are
identified molecule which is obtained by this process is imatinib which is
selective tyrosine kinase inhibitor it example of Pharmacophore model
5α-reductase which is essential in biosynthesis of testosterone
Virtual screening can utilize several computational techniques
depending on the amount and type of information available about the
compounds and the target. Like protein based method are used if the
3D structure of the target is known, Ligand based methods are used if
compound is found to be active or inactive for a specific target,
structural similarities are used if information about activity of few
compounds is known and machine learning methods like discriminant
analysis is used if activity of several compounds is known.
After performing the screening hit-leads are obtained further screening
of these hits to obtain drug-like compound is done by invitro techniques
using virtual well. These well are also called as micro titer well’s as
these are mostly used by immunologists for their assays. it consist of 96
well’s were each well represents the Petri plate(for comparison) where
drug and the target assay mixture is added, maintained at necessary
conditions required for binding of the compound and check for finding
the change in color if binding occurs by using the radio immuno
assay .these is mainly to screening the compound by their ability to bind
to the target further screening is done by in vivo where mostly one
molecule found to have necessary binding ability and action required.
With this, the drug-like compound is obtained and the drug discovery
process ends with the start of drug development which consist of
various phases of clinical trails in phase1 trial mainly physicochemical
patterns of the drug is checked, phase2 includes testing of the
compound on the patients and phase3 is testing on healthy volunteer if
the compound crosses all these clinical barriers it is patented by the
concerned industry, manufactured and enters the market. After entering
the market generally phase4 clinical trials is done to identify any long
term side effects is occurring, if so necessary actions can be taken.
Conclusion: virtual screening provides a short cut to drug discovery with
less cost and short period of time how ever the effectiveness of this
method depend on the collection of large data of previous molecules for
further prediction. in short it is more like aiming at target with guessing