De novo drug design
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Pharmacogenomics & Drug Design de novo de novo Drug Design Drug Design S.Prasanth Kumar, S.Prasanth Kumar, Bioinformatician Bioinformatician S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA www.facebook.com/Prasanth Sivakumar FOLLOW ME ON ACCESS MY RESOURCES IN SLIDESHARE prasanthperceptron CONTACT ME prasanthbioinformatics@gmail. com
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De novo drug designing strategies
Transcript of De novo drug design
S.Prasanth Kumar, S.Prasanth Kumar, BioinformaticianBioinformatician
Pharmacogenomics & Drug Design
de novode novo Drug Design Drug Design
S.Prasanth Kumar, S.Prasanth Kumar, BioinformaticianBioinformatician
S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA
www.facebook.com/Prasanth Sivakumar
FOLLOW ME ON
ACCESS MY RESOURCES IN SLIDESHARE
prasanthperceptron
CONTACT ME
From Scratch
DE NOVO DESIGNThe design of bioactive compounds by incremental construction of a ligand model within a model of the receptor or enzyme active site, the structure of which is known from X-ray or NMR data
a de novo design program
how to assemble the candidatecompounds; how to evaluate their potential quality;how to sample the search space effectively.
Primary Target Constraints
PRIMARY TARGET CONSTRAINTS(The binding affinity of a ligand to the particular biological target)
Receptor-based
Derivation of Interaction Site
Ligand-based
(subdivided into hydrogen bonds, electrostatic and hydrophobic interactions)
HSITE – hydrogen acceptor–donor pairsHIPPO - lipophilic
Receptor-based scoring
Scoring functions rank the generated structures and thereby suggest which structures are the most promising ones
Force fields: Energy Minimization LEGEND
Empirical scoring functions are a weighted sum of individual ligand–receptor interaction types commonly supplemented by penalty terms, such asthe number of rotatable ligand bonds.LUDI
Knowledge-based scoring is grounded on a statistical analysis of ligand–receptor complex structures. The frequencies of each possible pair of atoms in contact to each other are determined.SmoG
Ligand-based scoring
Particular biological target is unavailable but one or more binding moleculesare known
HO
H3C
Pseudo-Receptor
PharmacophoreHO
H3C
Secondary Target Constraints
Constraints other than the binding affinity are secondary constraints.
Candidate compounds with an increased chance of oral bioavailability can be obtained by filtering the designed structures with Lipinski’s rule of-five
A list of undesirable substructures for ease in the synthesis
Principles of structure-based ligand assembly
Link/grow strategy
Principles of structure-based ligand assembly
Lattice strategy
Search Space Exploration
Why De novo Drug Design ?
Complementary strategy to HTS
NCEs that were designed taking into consideration several aspects oflead- and drug-likeness and synthetic accessibility
De novo design offers a broader exploration of chemical space and therefore makes it possible to identify novel ligand scaffolds
