If we encounter a situation, where one can construct a pharmacophore model via multiple-complex based as well as via Molecular dynamics based. What is the best way to proceed further and which one is the most reliable?
Thanks Anum, Could you please send me the reference(s) regarding the same.
https://www.dovepress.com/structure-based-three-dimensional-pharmacophores-as-an-alternative-to--peer-reviewed-fulltext-article-JRLCR
Dear Anum,
Have gone through this article but, couldn't find the answer.
both the modeling techniques are useful but the limitations of Ligand based are more than the complex based as following
several key challenges in ligandbased pharmacophore modeling .
1. The first challenging problem is the modeling of ligand flexibility
2. Molecular alignment is the second challenging issue in ligandbased pharmacophore modeling
3. Another challenging problem lies in the practical task of proper selection of training set compounds
4. It may be possible that an active molecule cannot be identified if the conformation is missing
5. Different rotations might be very hard to be distinguished during the conformation generation
etc.
where as there is only one limitation of complex based pharmacophore modeling i-e
1. too many chemical features can be identified for a specific binding site of the macromolecular target. A pharmacophore model composed of too many
chemical features is not suitable for practical applications, such as 3D database screening.
the solution to this problem is to select a limited number of chemical features
to construct a practical pharmacophore. you can also overcome this signle issue by creating multicomplex-based comprehensive map and most-frequent pharmacophore model
Thanks dear for your sincere efforts but, the question asked is miles apart.
Dear Mohsin,
As per my level of understanding, both methods are optimal and its difficult to decide which one is better, in general. As both have their pros and cons.
Using complex based method, ambiguities regarding the overall functional features of complex can be avoided as most of the features (interacting atom types and their positions) will be taken into account. However, with the Dynamics based, flexibility and structural rigidity of the complex will be considered.
I think it depend on the type of protein-ligand complex (you want to model), that subsequently will decide the excellency of the method.
Hope this will help !!
regards
athar
Hi
For pharmacophore model development, I would prefer multiple-complex based method using the PHASE module in Schrodinger's software:
Here is the link:
https://www.researchgate.net/publication/312187591_Mechanistic_Insights_into_the_Binding_of_Class_IIa_HDAC_Inhibitors_toward_Spinocerebellar_Ataxia_Type-2_A_3D-QSAR_and_Pharmacophore_Modeling_Approach
Article Mechanistic Insights into the Binding of Class IIa HDAC Inhi...
Dear Siddharth Sinha,
I didn't find any relevance of the suggested reference with the query. Could you please help me to understand the same.
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