If this library is prepped for docking i. This breaks down as: In terms of data storage, a 7. In the same vein, preparing the fully enumerated file required 14 hours. Whereas the simple enumeration no additional stereoisomers generated required 23 minutes. Clearly, in larger libraries this problem will be more pronounced even if the specific increases in time required for preparation will vary between computers.
Lacking a priori knowledge of which compounds would serve as actives from a library, a virtual screening campaign relies on a thorough exploration of the chemical space represented by the structure database. This includes alternate tautomers, ionization states, and stereoisomers. However thorough exploration of all the potential stereoisomers in a library can be prohibitive in terms of time, data storage, and library management. While the ideal situation is to include every feasible stereoisomer, analysis of the effects of stereoisomer structures on docking poses suggests that enantiomeric pairs are sufficient for exploration of chemical space [ 31 ].
The ability to include only enantiomeric pairs depends on the quality of the structure library [ 31 ]. However, a library that possesses stereochemical information, albeit relative stereochemistry, is more suitable to enantiomeric extrapolation and confidence can be maintained that additional diastereomers are not relevant to the structure library. This provides a compromise between fully exploring chemical space and keeping structure libraries manageable in terms of numbers of structures, data storage, and time requirements for preparations and dockings.
Previously we reported that the docking of nutlin-2 to MDM2 was strongly dependent on which enantiomer was docked [ 31 ]. We examined nutlin-2 PDB: These compounds and their enantiomers give a variety of outcomes based on the degree to which the chiral carbon s affects the overall geometry of the compound. After docking, consistent with earlier observations, the R,S nutlin the co-crystalized form docked at rank 51, whereas the enantiomer docked at rank 3, out of 3, structures.
Likewise, the estimated binding energy worsened from The RMSD between the two docking poses was 7. This coincides with what was previously reported and shows that when chirality has a strong influence on the geometry of the molecule the docking pose will vary dramatically between enantiomers [ 31 ].
This suggests that geometric changes caused by a change in chirality could be absorbed due to the flexibility of the chain, which bears out in docking results. Rank 2 and Additionally, the docking poses are almost identical with an RMSD of 0. In this case, the chiral carbon has some influence on the overall geometry of the molecule and its resulting docking pose.
R,S Sertraline comes in at rank 67 out of 3, docked structures while the S,R enantiomer ranks This demonstrates that a moderate difference in binding pose due to chirality can result in dramatic ranking shifts within a library. These observations provide insight into the behavior of enantiomeric pairs within a structure library during docking. Clearly, there is no hard and fast rule to how an enantiomeric pair will behave. It is equally clear that when a chiral atom influences a compound's geometry or binding pose i.
Thus, important lead compounds can be missed as false negatives if the appropriate enantiomer was not included in the structure library.
Additionally, even when absolute stereochemistry is known and the target is enantioselective then enantiomers serve as excellent decoy molecules during docking and can be added to a structure database such as the Directory of Useful Decoys [ 36 ]. Computational software is likely to either create all possible stereoisomers or some user imposed limit thereof or to generate structures based on the chiral notations in the input structure file. However, none of these is going to give only the enantiomeric partner of a compound. As is apparent, Ligprep will either generate a single structure based on the chiral information from the SDfile or will generate all possible stereoisomers.
Thus, a specific method of generating only enantiomeric partners should be employed to avoid the complications of library growth and time requirements of the docking simulation as discussed in section 2. If a file of small molecule 3D structures lacks the enantiomeric partners for the chiral molecules, the missing structures can be generated by creating a fairly simple script or program to parse through the file, identify each chiral structure, and then output a copy of that structure to a second file, multiplying the Z coordinate by -1, as shown in Fig.
The two files can then be concatenated if desired to create a single file with both stereo enantiomers represented.
Each situation will be dependent on the type of file format involved and the programming ability of the user. Generating a stereo enantiomer. If the coordinates for one chiral molecule are available, the other stereo enantiomer can be created by simply multiplying the Z coordinate by When three of the four substituent first-level atoms of a chiral center are superimposed, it simplifies the relationship between the enantiomers such that you only need to multiple the Z coordinate of every atom by -1 to generate the missing stereo enantiomer.
As an example, we generated enantiomers for the NCI Diversity Set I, which contains 1, compounds of which had chiral centers [ 31 ]. Stereo enantiomers were then created from the LigPrep processed file using a Perl script that we coded. This script parsed through each record of a structure to interrogate a field that flagged chirality. Of the structures extracted from the NCI Diversity Set, were successfully converted into the enantiomeric partner. The structures that failed this conversion we believe were large meso-compounds that presented difficulties for our simple PERL script to handle.
As meso-compounds they have a symmetry which means that, inspite of having chiral centers, the two partners are superimposable and, therefore, would rank the same in virtual docking. The purpose of the exercise was to compare rankings when the enantiomeric partners differed. The purpose of our work was to study and report the differences in Glide Score rankings that can occur between enantiomers. Chirality in drug discovery and development has increased in importance since guidelines for chiral compounds in drug development and approval were issued by regulatory agencies in the timeframe.
The guidelines were issued due to the potential differing activities of enantiomers in chiral compounds. Although enantiomers will have the same properties in achiral environments, the effects can be quite different in biological environments where enzymes and receptors can be chirally selective.
In some cases, the presence of the distomer in a racemic mixture can affect the results due to detrimental effects of the distomer or its conversion to the eutomer configuration. The composition of the racemic mixture and its potential to change with time or depending on the system and tests ex.
As a result of the guidelines and regulations, the onus is on the investigators initiating drug discovery projects to determine early in the project whether to pursue racemates or enantiomerically pure compounds; with emphasis on enantiomerically pure compounds. To this end there are several important considerations in the early stages of a drug discovery project. While, crystallography is the gold standard for examining protein structure and compound binding there are limitations and costs associated with it.
For example, there is a need for a relatively potent compound in order to achieve co-crystallization. A potent relevant compound may not be available in the early stages. As a result, very powerful tools available for lead discovery and refinement are virtual screening and molecular modeling. Virtual screening and molecular modeling methods enable the rapid identification of lead compounds using calculated free energies of binding.
However, due to the vagaries of diastereomers and their binding modes it is vital to start with accurate stereochemical depictions of compounds in virtual compound libraries used as an initial step in identifying potential drug candidates. Ideally, investigators should incorporate every possible stereoisomer in their databases. However, realistically this can lead to significant increases in time and management issues for those databases. Alternatively, if the original compound database does contain stereochemical information, then generation of enantiomeric partners is sufficient for exploration of chemical space based on the library and for including decoy molecules.
In many cases, missing enantiomers can be generated with a minimal programming effort by a drug discovery team. The underlying key to virtual screening is to balance exploration of chemical space, data storage, and time needed to screen. All of these issues from biological, intellectual property, regulatory, and laboratory both virtual and physical development strategies underscore the importance of considering stereochemistry, in gereral, and chirality, in particular, before embarking on and during a drug discovery campaign.
National Center for Biotechnology Information , U. Curr Top Med Chem. Author manuscript; available in PMC Jan Brooks , 1 W. Guida , 1, 2 and K. The publisher's final edited version of this article is available at Curr Top Med Chem. See other articles in PMC that cite the published article. Abstract Proteins are often enantioselective towards their binding partners.
Chiral, virtual screening, drug design, drug discovery, FDA guidelines, enantiomer, in silico, computational chemistry. Introduction The purpose of a drug discovery and development project is to find new therapeutic agents that target a key enzyme, protein-protein interaction, receptor-ligand, or protein-nucleic acid interaction of relevance in a disease of interest in order to mitigate the course of the disease.
Chirality Defined Chirality can be defined as the potential of a molecule to occur in two asymmetric forms that are non-superimposable mirror images of each other without changing the atomic composition, atom-atom connections, or bond orders Fig. Open in a separate window.
Properties of Chiral Compounds Enantiomeric pairs will have the same mass, atomic composition, melting points, boiling points, and other physical characteristics will be the same except for the rotation of polarized light but, as a left-hand glove does not properly fit the right hand, chiral molecules can induce stereoselectivity into the reactions and interactions in which they participate.
Regulatory Guidelines The United States Food and Drug Administration FDA did not require drug evaluations until , at which time new drugs had to demonstrate effectiveness to meet approval. Due to this, there are several potential scenarios that could exist: The enantiomers that make up the racemic mixture have similar effects. The enantiomers that make up the racemic mixture have differing effects and there can be enatiomeric drift in a chiral environment, such as in a biological setting, so that the original racemic The racemate contains an effective eutomer but the distomer has detrimental effects that must be eliminated.
An enantiomerically pure compound undergoes partial or complete racemization in vivo or ex vivo resulting in formation of at least some of the distomer. Trends in Chiral Drugs 2. Chiral Switching Based on these new guidelines in the 's, most drug companies and research institutes have begun focusing on single enantiomers early on when they identify a chiral drug candidate.
The Chiral Drug Market Many of the top selling drugs have been marketed as single enantiomer drugs, such as Fluticasone GlaxoSmith-Kline for respiratory therapeutics and Pravastatin Bristol-Myers Squibb for cardiovascular therapeutics [ 17 ]. Practical Concerns of Stereochemistry in Early Drug Development A common theme of the regulatory guidelines is that questions of stereochemistry should be addressed early in a drug discovery project.
Examination of Chiral Selectivity with Physical Methods In some situations, an enzyme may be able to handle either enantiomer but use a quite different spatial means of accommodating each enantiomer. Examination of Chiral Selectivity with Computational Methods In drug discovery programs virtual screening is maturing into a powerful tool [ 23 ].
Characteristics of Chemical Structure Libraries Due to the costs and difficulty of chiral selective synthesis, optically active compounds are often synthesized as racemates.
Effects of Stereoisomers on Library Management Lacking stereochemical information and alternative stereoisomers is not a short-coming of these databases. Effects of Including Enantiomers in Virtual Screening Lacking a priori knowledge of which compounds would serve as actives from a library, a virtual screening campaign relies on a thorough exploration of the chemical space represented by the structure database. Generation of Enantiomeric Pairs for Structure Library Files Computational software is likely to either create all possible stereoisomers or some user imposed limit thereof or to generate structures based on the chiral notations in the input structure file.
Specifically Generating Enantiomeric Partners to Compounds with Chiral Centers If a file of small molecule 3D structures lacks the enantiomeric partners for the chiral molecules, the missing structures can be generated by creating a fairly simple script or program to parse through the file, identify each chiral structure, and then output a copy of that structure to a second file, multiplying the Z coordinate by -1, as shown in Fig. Conclusions Chirality in drug discovery and development has increased in importance since guidelines for chiral compounds in drug development and approval were issued by regulatory agencies in the timeframe.
Protein structure prediction in structure-based ligand design and virtual screening. Comb Chem High Throughput Screen. Development of new stereoisomeric drugs. Caldwell J, Wainer IW. Reddy I, Mehvar R, editors. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol.
Chiral non-steroidal anti-inflammatory drugs — a review. J Indian Med Assoc. Putting chirality to work: Toggle navigation Additional Book Information. It supports researchers as they evaluate the pharmacodynamic, pharmacokinetic, and toxicological characteristics of specific enantiomers and chiral drug compounds and addresses in one convenient reference all the major challenges pertaining to drug chirality that have been neglected in the literature. Chirality in Drug Design and Development collects the latest studies from an interdisciplinary team of experts on chiral drug design.
Request an e-inspection copy. Photostability of Drugs and Drug Formulations. The Bookshelf application offers access: Offline Computer — Download Bookshelf software to your desktop so you can view your eBooks with or without Internet access. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present.
Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects.
This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid.
From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance. National Center for Biotechnology Information , U.
The existence of the enantiomer is typically implied in such cases as the enantiomer is unlikely to be literally listed in the file and diastereomers may need to be added as well discussed below. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. As of , governmental regulations on drug safety and efficacy have become stricter with regard to compounds that have stereochemistry [ 3 ]. Chem Des Auto News. When attempting to superimpose these versions, there will always be at least one substituent attached to the chiral atom that cannot be superimposed. National Center for Biotechnology Information , U.
Didn't get the message? Add to My Bibliography.