1. Drug Evolution
Hybridization method
M.sc. Student Sanad Alfadhel

2. Evolution Theory
and yet it moves - Galileo

3. Introduction
In response to the new molecular targets and ever-increasing global competition, new drugs must be developed in a short period of time.
Furthermore, the era of continuous growth and profitability of the pharmaceutical industry is coming to an end due to the high costs of drug development ($800 million/drug).
Thus, methods for rapid and cost-effective drug development are in urgent need.

4. Drug desin tools
Pharmaceutical Industry has invested heavily in the development of new techniques of diagnosis, investigation and creation of chemical libraries with high molecular diversity, based on :
combinatorial chemistry,
computer-aided drug design (CADD),
(QSAR),
automatized processes of pharmacological screening (High Throughput Screening – HTS),
biotechnological approaches.
Recently, the natural products chemistry has been returning to a prominent position in the prospection of bioactive compounds,

5. Drug desing
However, the high cost of the general chemical library and HTS can be a problem. Even if the cost of each chemical and the cost of assay per chemical is low, screening compounds, which is the typical size of HTS in the pharmaceutical industry, may cost up to millions of dollars.
The quality of the chemicals and the number of compounds in libraries were improved by excluding nondruglike molecules.(depending on rule of five)
This substantially reduced the cost of synthesis. Furthermore, many druglike molecules are commercially available at relatively low cost per compound.

7. Molecular hybridization
is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with improved affinity and efficacy, when compared to the parent drugs.
Additionally, this strategy can result in compounds presenting :
modified selectivity profile,
different and/or dual modes of action
and reduced undesired side effects

8. Hybridization method
It does not depend on whether the new target is homologous to the known targets or not, was proposed by Holland.
He converted biological evolution to chemical evolution and used optimization techniques called genetic algorithms (GAs), which are evolutionary search and optimization strategies jbased on the Darwinian model of natural selection and evolution.

9. The biological evolution methods could be sexual recombination of parental genes, mutation, chimera, horizontal gene transfer, etc.

10. As an initial trial of the drug evolution, we selected parent molecules that had the same scaffold. The same scaffold may be regarded as the restriction of the sexual recombination between male and female of one species
p-aminobenzoic acid (PABA) as a scaffold to generate general chemical libraries

11. the PABA scaffold shows up frequently in the structure of drugs, as 184 drugs among drugs in the Negwer's database7 retain the structure of PABA
the PABA-containing drugs show diverse therapeutic activities as 84 therapeutic applications are listed in Negwer's database,
the scaffold fits to easy combinatorial synthesis as PABA contains two reactive functional groups (carboxyl and amino groups), and
the possibilities of designing novel PABA-containing compounds are very high. For example, just by shuffling the building blocks used in 184 PABA-containing drugs at the corresponding substitution sites, 4 million compounds, most of them novel, can be generated.

12. Meticlopramide
Benzocaine

15. Conclusions
A new concept, drug evolution is introduced. It incorporates the methods of biological evolution into drug development. This concept consists of evolving the existing drugs in order to develop new ones, in particular drugs and drug candidates corresponding to a wide range of diseases or medicinal targets, and to design general libraries of such compounds, drug evolution libraries. The sexual recombination of parental genomes in biological evolution was successfully used to build two sets of drug evolution libraries that use PABA and salicylic acid as scaffolds. The libraries were validated as the hybridization of the parental drugs generated drug(s).
Indeed, 50% of the 16 compounds in the PABA hybridization library are drugs or drug candidates.
The probability of finding drug(s) or drug candidate(s) within the remaining molecules of the libraries is high in such drug-enriched libraries

16. Refrences
Drug Evolution Concept in Drug Design: 1. Hybridization Method² Carmen Lazar, Alicja Kluczyk,³ Taira Kiyota, and Yasuo Konishi* Biotechnology Research Institute, 6100 Royalmount Avenue, Montreal, Quebec, Canada H4P 2R2 Received May 17, 2004
Molecular Hybridization: A Useful Tool in the Design of New Drug Prototypes Cláudio Viegas-Junior1, Amanda Danuello1, Vanderlan da Silva Bolzani1, Eliezer J. Barreiro2 and Carlos Alberto Manssour Fraga*,2 1Instituto de Química, Universidade Estadual Paulista “Júlio de Mesquita Filho”, P.O. Box 355, Araraquara, São Paulo, SP, Brazil 2Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, P.O. Box 68023, , Rio de Janeiro, RJ, Brazil

17. Thank you