Module 6 Computer Aided Drug design & Preformulation studies

Question 1

The inventive process of finding new medications based on the knowledge of a biological target.

Answer 1

Drug Design

Question 2

It involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it.

Answer 2

Drug Design

Question 3

LIFE CYCLE OF DRUG DESIGN:
Traditional Life Cycle

Answer 3

Ist step: Synthetic Or natural product
2nd step: Preclinical trials
3rd step: Clinical trials
Drug

Question 4

LIFE CYCLE OF DRUG DESIGN:
Modern Drug Design

Answer 4

Ist step: Target Selection
2nd step: Lead Identification
3rd step: Lead Optimization
Drug

Question 5

DRUG DESIGNING:
Selected/ design molecules should be:

Answer 5

•Organic small molecule
•Complementary in shape to the target
•Oppositely charge to the biomolecular target

Question 6

DRUG DESIGNING…
This molecule will:

Answer 6

•Interact with the target
•Bind to the target
•Activates or inhibit the function of a biomolecule such as protein

Question 7

DRUG DESIGNING:
Drug designing frequently but not necessarily relies on computer modelling techniques.
This type of modelling is sometimes referred to as computer aided design.

Answer 7

N/A

Question 8

Drug discovery approaches:

Answer 8

In Vitro
1. Biochemical estimation
2. Toxicity asay
3. Assays on drug susceptibility
4. Effects on biofilm

In Vivo
1. Bioavailability
2. Toxicity
3. ADME
4. Pharmacodynamics
5. Pharmacokinetics

In Silico
1. Computer-aided drug discovery
2. Molecular docking
3. Molecular modeling
4. Virtual screening
5. Quantitative structure–activity relationship (QSAR)

Question 9

The term ‘____’ is a modern word usually used to mean experimentation performed by computer and is related to the more commonly known biological terms in vivo and in vitro.
Process, identification of the suitable drug target is the first and foremost task.
These targets are biomolecules which mainly include DNA, RNA and proteins (such as receptors, transporters, enzymes and ion channels).

Answer 9

in silico

Question 10

uses computational approaches to discover, develop, and analyze drugs and similar biologically active molecules.

Answer 10

COMPUTER-AIDED DRUG DESIGN (CADD)

Question 11

Computer-aided drug discovery
Characteristic features of CADD:

Answer 11

Virtual screening
Energy calculations
ADME models
Drug interactions

Question 12

2 CATEGORIES OF “IN SILICO” BASED DRUG DESIGN:

Answer 12

Ligand-based drug design
Structure-based drug design

Question 13

The basic objective of these methods is to predict the nature and strength of binding of given molecule to a target.

Answer 13

Ligand-based drug design

Question 14

Involves the analysis of ligands known to interact with a target of interest.
These methods use a set of reference structures collected from compounds known to interact with the target of interest and analyze their 2D or 3D structures.
This is an indirect approach where analysis is totally dependent on information of other molecules that attach to the target compound of interest.

Answer 14

Ligand-based drug design

Question 15

These other molecules may be used to develop a pharmacophore model that delineates the minimum needed structural characteristics a molecule must hold in order to bind to the target successfully.
Precisely a model of the biological target may be constructed on the facts of what binds to it.
This knowledge could be further implemented to design new molecular entities that interact with the target.

Answer 15

Ligand-based drug design

Question 16

This is relatively a direct approach which is based on the knowledge of the three-dimensional structure of the biological target obtained through methods such as X-ray, crystallography, or NMR spectroscopy which are mainly the starting point for gathering information in the field of drug discovery and development

Answer 16

Structure-based drug design

Question 17

In case of unavailability of the target structure, prediction using a related protein’s experimental structure is carried out by generating a homology model of the target.
Based on this data drug that seems to be exhibiting high affinity for the target is selected and further computational trials are employed to suggest new drug candidates.

Answer 17

Structure-based drug design

Question 18

It works with the basic understanding of structure prediction of intermolecular complex formed between drug and its target molecule.
It gives other important information like extent and specificity of interaction, binding and transformation energies.

Answer 18

MOLECULAR DOCKING

Question 19

is a pharmacologically important tool in the field of drug designing and computational biology

Answer 19

Docking

Question 20

A method of comparing and analyzing molecular structures, 3D structure-based properties, and their interactions.
Primary applicability of this technique generates data on receptor ligand interaction, protein-protein interactions, 3D structure prediction, and based on this predicting biological function of related compounds.

Answer 20

MOLECULAR MODELING

Question 21

The key methodology applied in drug discovery studies for the identification of new hits.
Receptor structure based as well as non receptor based methods could be employed to design ligand

Answer 21

VIRTUAL SCREENING

Question 22

establishes a relation between predictor and response variables by applying graphical and mathematical models.
For prediction and evaluation of compound binding modes mathematical relationships between structural attributes and target properties of a set of chemicals are studied

Answer 22

Quantitative structured activity relationship (QSAR)

Question 23

is a group of studies that focus on the physicochemical properties of a new drug candidate that could affect the drug performance and the development of a dosage form.
This could provide important information for formulation design or support the need for molecular modification.

Answer 23

Preformulation studies

Question 24

The overall objective of pre formulation testing is to generate information useful to the formulator in developing stable and bioavailable dosage forms which can be mass-produced

Answer 24

N/A

Question 25

Before starting the preformulation studies, we should know the:

Answer 25

•Properties of the drug.
•Potency relative to the competitive products and the dosage form.
•Literature search providing stability and decay data
•Proposed route of drug administration.
•Literature search regarding the formulation approaches.
•Bioavailability
•Pharmacokinetics of chemically related drugs.

Question 26

Other requirements for preliminary studies:

Answer 26

1. Preliminary investigations
2. Molecular optimization by the drug
3. A molecular modification should be done (if a deficiency is detected).

Question 27

To overcome this deficiency molecular modification is done be salts, prodrugs, solvates, polymorphs or even new analogues.
The dissolution rate of a salt form of a drug is generally quite different from that of the parent compound.

Answer 27

N/A

Question 28

Physicochemical parameters:

Answer 28

Organoleptic properties
Bulk characterization studies
Solubility analysis
Stability analysis

Question 29

Organoleptic properties:

Answer 29

individual experience via the senses—including taste, sight, smell, and touch.
It refers to the methods of analysis like colour, odour, taste, size, shape and special features, such as touch, texture, etc.

Question 30

Bulk characterization studies:

Answer 30

Bulk characterization studies:
a) Crystallinity and polymorphism
b) Hygroscopicity
c) Fine particle characterization
d) Bulk density
e) Powder flow properties
f) Compression properties
g) Physical description

Question 31

Solubility analysis:

Answer 31

a) Intrinsic solubility determination
b) PKa determination
c) Partition coefficient
d) Dissolution studies
e)Common ion effect

Question 32

Stability analysis:

Answer 32

a) In toxicology formulations
b) Solution stability
c) Solid state stability

Question 33

EVALUATION PARAMETERS USED IN PREFORMULATION OF DRUG DEVELOPMENT:

Answer 33

1. Stability, Solid State, Solution - Temperature, Light, humidity Solvent, Ph
2. Solid State Compatibility - TLC and DRS Analysis
3. Physico-chemical Properties Color, odor, particle size, shape crystallinity - Molecular Structure and Weight, melting point
4. •Thermal Analysis Profile - DTA DSC,TGA
   •Water and other solvent, pH - Salt forms, co-solvent, Complexation, pro-drug
5. Absorbance Spectra - UV, IR
6. Other properties Hygroscopicity - Potential Bulk characterization Volatility, optical activity, solvate formation Crystallinity and polymorphism.
7. Physico-mechanical Properties Bulk and - Tapped density, compressibility Photomicrograph
8. In Vitro Availability Properties, Rat Everted Gut Technique - Dissolution and analysis of Drug Crystal pallets
9. Other Studies Plasma Protein Binding, lonization Constant - Effect of Compatible Excipients on dissolution Kinetic Studies of Solution Degradation, Use of Radiolabeled Drug