In drug discovery there are various in silico approaches such as Virtual high throughput screening, Molecular docking, Homology modelling, QSAR, CoMFA, Molecular Dynamics, and Pharmacophore mapping. In this presentation various limitations of these approaches are given

1. Limitations of In silico methods
Presented by:
Alichy Sowmya
18PIM2855
M.S.(Pharm.) 1 st sem
Department of Pharmacoinformatics
NIPER , S.A.S Nagar

2. 1
In silico
approaches in
Drug discovery
Structure Based
Approaches
Homology
Modelling
Molecular
Docking
Virtual high-
throughput
screening
Ligand Based
Approaches
QSAR
CoMFA (3D
QSAR)
Pharmacophore
Mapping
Molecular
dynamics

3. Limitations of Virtual high throughput screening
• Conformational sampling is limited
• Time available for each docking is less than a minute
• The size of database decides the number of molecule that can be treated in
reasonable amount of time
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Limitations of Docking:
• Flexible ligands – combinatorial explosion
• Solvation
• Protein Flexibility – Induced fit
• Tautomers, Water Molecules

4. Limitations of QSAR:
• Bioactive conformation and alignment
• Biological effects are neglected
• Applicable only to In vitro data
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Limitations of Homology Modelling
• Templates are often unavailable, or fragmentary
• Errors and uncertainties in the sequence alignment produce errors in the
homology model
• Sidechain rotamer positions will be incorrect

5. Limitations of Pharmacophore Mapping:
• Absence of good scoring metrics
• Dependency on Precomputed Conformation base
• No one clear way to construct a pharmacophore query
Limitations of CoMFA:
• Bioactive conformation and alignment
• Initial Structure Should be Bioactive
• Hydrophobicity is not well quantified
• Applicable only to In vitro data
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6. Limitations of Molecular Dynamics(MD):
• Timescale
• Covalent Bonds can not form or break during MD simulations
• Force field accuracy
• Electronics degree of freedom are neglected
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