Computational alchemy in drug discovery involves potential energy function,
and the development of potential functions still continues to tackle various situations. Knowledge of structural waters is useful in inhibitor design.
In structure-based drug design (SBDD), the three-dimensional structure of
bioactive agents and their targets are the bases. There are many approved drugs, like
AIDS medications Crixivan and Viracept, the flu drug Tamiflu, the leukemia
therapy Gleevec, and the cancer agent Tarceva, which have come out through
SBDD. X-ray crystallography and NMR spectroscopy are very much useful in
knowing the three-dimensional molecular structures which play a crucial role in
SBDD. Important antibiotics with the targets lipid II and ribosome 50’s subunit
have come out using SBDD. Using modeling programs like Analog and QikeProp,
many antibiotics are in human clinical trials. X-ray crystal structure of Human
Immunodeficiency Virus Reverse Transcriptase (HIV-RT) and the complexes with
various antiviral drugs, diarylprimidines, have been discovered as promising inhibitors and some of these are in phase II and phase III trials. In structural-based
vaccine design, at Rutgers University, the first structure of a virus that infects
animals, the cold-causing human rhinovirus, has been obtained, and its modified
form in complex with an anti-HIV antibody was used as the basis [18]. For Tumor
necrosis factor-Alpha-Converting Enzyme (TACE), novel hydroxamates were
developed using X-ray crystallography in combination with structure–activity
relationship (SAR). TACE inhibitors are potential anti-inflammatory agents. X-ray
crystallography along with molecular modeling has been used to identify potent and
selective inhibitors of human beta-secretase-1 (BASE–I). Alzheimer treatment and
selective oral chymase inhibitors for asthma and dermatitis have entered clinical
trials where SBDD was used. Since 25% of genes code for membrane proteins like
G Protein-Coupled Receptors (GPCRs), these are highly important targets for
SBDD. Unfortunately, these membrane proteins are hard to isolate and crystallize.
Due to the difficulties in crystallization and not many three-dimensional structures
are available, molecular modeling has helped to develop potent inhibitors of
glycogen phosphorylase, the target for designing anti-diabetic drugs. Using SBDD
approach, compounds were designed with 3- to 14-fold better potency than the lead
compound. Recently, fragment-based approaches (FAPs) are used in SBDD. Using
the combination of fragment screening, computational chemistry, and structural
biology for fragment-based drug discovery, a compound was synthesized and went
to clinical trial approval in just 14 months and went to the phase I clinical trial
treatment of refractory solid tumors. Like the above, there are many examples
showing how many potent drugs have come out using SBDD approach.
2 Role of X-Ray Crystallography in SBDD and Medicine
Crystallography as a science and as a diffraction technique had started and grown
exponentially after the famous Laue experiment. The diffraction experiment elucidates the structure and arrangement of atoms/molecules, which form a perfectly
Structure-Based Drug Design…
273
and the development of potential functions still continues to tackle various situations. Knowledge of structural waters is useful in inhibitor design.
In structure-based drug design (SBDD), the three-dimensional structure of
bioactive agents and their targets are the bases. There are many approved drugs, like
AIDS medications Crixivan and Viracept, the flu drug Tamiflu, the leukemia
therapy Gleevec, and the cancer agent Tarceva, which have come out through
SBDD. X-ray crystallography and NMR spectroscopy are very much useful in
knowing the three-dimensional molecular structures which play a crucial role in
SBDD. Important antibiotics with the targets lipid II and ribosome 50’s subunit
have come out using SBDD. Using modeling programs like Analog and QikeProp,
many antibiotics are in human clinical trials. X-ray crystal structure of Human
Immunodeficiency Virus Reverse Transcriptase (HIV-RT) and the complexes with
various antiviral drugs, diarylprimidines, have been discovered as promising inhibitors and some of these are in phase II and phase III trials. In structural-based
vaccine design, at Rutgers University, the first structure of a virus that infects
animals, the cold-causing human rhinovirus, has been obtained, and its modified
form in complex with an anti-HIV antibody was used as the basis [18]. For Tumor
necrosis factor-Alpha-Converting Enzyme (TACE), novel hydroxamates were
developed using X-ray crystallography in combination with structure–activity
relationship (SAR). TACE inhibitors are potential anti-inflammatory agents. X-ray
crystallography along with molecular modeling has been used to identify potent and
selective inhibitors of human beta-secretase-1 (BASE–I). Alzheimer treatment and
selective oral chymase inhibitors for asthma and dermatitis have entered clinical
trials where SBDD was used. Since 25% of genes code for membrane proteins like
G Protein-Coupled Receptors (GPCRs), these are highly important targets for
SBDD. Unfortunately, these membrane proteins are hard to isolate and crystallize.
Due to the difficulties in crystallization and not many three-dimensional structures
are available, molecular modeling has helped to develop potent inhibitors of
glycogen phosphorylase, the target for designing anti-diabetic drugs. Using SBDD
approach, compounds were designed with 3- to 14-fold better potency than the lead
compound. Recently, fragment-based approaches (FAPs) are used in SBDD. Using
the combination of fragment screening, computational chemistry, and structural
biology for fragment-based drug discovery, a compound was synthesized and went
to clinical trial approval in just 14 months and went to the phase I clinical trial
treatment of refractory solid tumors. Like the above, there are many examples
showing how many potent drugs have come out using SBDD approach.
2 Role of X-Ray Crystallography in SBDD and Medicine
Crystallography as a science and as a diffraction technique had started and grown
exponentially after the famous Laue experiment. The diffraction experiment elucidates the structure and arrangement of atoms/molecules, which form a perfectly
Structure-Based Drug Design…
273