Biomedical subjects

Alan C Cheng

Publications and source records attributed to Alan C Cheng.

7 recordsLinked to original sources

PubMed2007

Structure-based maximal affinity model predicts small-molecule druggability.

Lead generation is a major hurdle in small-molecule drug discovery, with an estimated 60% of projects failing from lack of lead matter or difficulty in optimizing leads for drug-like properties. It would be valuable to identify these less-druggable targets before incurring substantial expenditure and effort. Here we show that a model-based approach using basic biophysical principles yields good prediction of druggability based solely on the crystal structure of the target binding site. We quantitatively estimate the maximal affinity achievable by a drug-like molecule, and we show that these calculated values correlate with drug discovery outcomes. We experimentally test two predictions using high-throughput screening of a diverse compound collection. The collective results highlight the utility of our approach as well as strategies for tackling difficult targets.

Algorithms↗

PubMed2006

Optimal charges in lead progression: a structure-based neuraminidase case study.

Collective experience in structure-based lead progression has found electrostatic interactions to be more difficult to optimize than shape-based ones. A major reason for this is that the net electrostatic contribution observed includes a significant nonintuitive desolvation component in addition to the more intuitive intermolecular interaction component. To investigate whether knowledge of the ligand optimal charge distribution can facilitate more intuitive design of electrostatic interactions, we took a series of small-molecule influenza neuraminidase inhibitors with known protein cocrystal structures and calculated the difference between the optimal and actual charge distributions. This difference from the electrostatic optimum correlates with the calculated electrostatic contribution to binding (r(2) = 0.94) despite small changes in binding modes caused by chemical substitutions, suggesting that the optimal charge distribution is a useful design goal. Furthermore, detailed suggestions for chemical modification generated by this approach are in many cases consistent with observed improvements in binding affinity, and the method appears to be useful despite discrete chemical constraints. Taken together, these results suggest that charge optimization is useful in facilitating generation of compound ideas in lead optimization. Our results also provide insight into design of neuraminidase inhibitors.

Binding Sites↗

PubMed2005

An intuitive approach to measuring protein surface curvature.

A natural way to measure protein surface curvature is to generate the least squares fitted (LSF) sphere to a surface patch and use the radius as the curvature measure. While the concept is simple, the sphere-fitting problem is not trivial and known means of protein surface curvature measurement use alternative schemes that are arguably less straightforward to interpret. We have developed an approach to solve the LSF sphere problem by turning the sphere-fitting problem into a solvable plane-fitting problem using a transformation known as geometric inversion. The approach works on any arbitrary surface patch, and returns a radius of curvature that has direct physical interpretation. Additionally, it is flexible in its ability to find the curvature of an arbitrary surface patch, and the "resolution" can be adjusted to highlight atomic features or larger features such as peptide binding sites. We include examples of applying the method to visualization of peptide recognition pockets and protein conformational change, as well as a comparison with a commonly used solid-angle curvature method showing that the LSF method produces more pronounced curvature results.

Algorithms↗

PubMed2004

Ab initio interaction energies of hydrogen-bonded amino acid side chain[bond]nucleic acid base interactions.

Hydrogen-bonding interactions often make substantial contributions to the specificity of protein-nucleic acid complexes. Using a geometric modeling approach, we previously identified 28 possible doubly hydrogen-bonded interactions to the four unpaired RNA bases. Here we present interaction energies of these models, calculated by ab initio quantum chemical methods, and describe a correlation between the computed energies and observed frequencies of the interactions. In general, interactions with charged side chains show the most favorable energies. An Asp/Glu-G interaction may be especially favorable for recognition of unpaired guanines in RNAs. Asn and Ser/Thr/Tyr side chains are calculated to make iso-energetic interactions to the Hoogsteen face of adenine, but Asn-A interactions are much more common with DNA than RNA, and Ser/Thr/Tyr-A interactions are more common with RNA than DNA. Examination of the known interactions suggests that Ser/Thr/Tyr may be accommodated in a wider variety of protein contexts at RNA-protein interfaces. With these calculated intrinsic affinities, it should be possible to better assess the contributions of bidentate hydrogen-bonding interactions to RNA- and DNA-binding specificity.

Adenine↗

PubMed2003

Structural diversity and isomorphism of hydrogen-bonded base interactions in nucleic acids.

The wide structural diversity of RNA results in part from the diversity of non-Watson-Crick interactions between bases. To examine the repertoire of possible hydrogen bond interactions among bases, we computed databases of base-pairs and base-triples by systematically matching all possible hydrogen-bond donors and acceptors between bases and evaluating the geometries of each planar configuration. For base-pairs, we find 53 arrangements having at least two hydrogen bonds, including 23 pairs with protonated bases that have not previously been modeled. A comparison with experimentally observed base-pairs reveals an unexpected G:U pair recently observed in the ribosome. For base-triples, we find 840 arrangements in which the three bases are constrained by a total of at least three hydrogen bonds. Base-triples in particular exhibit a wide range of structural diversity, suggesting how compact or elongated nucleic acid structures may be constructed using different hydrogen-bonding patterns. Base-pair and base-triple conformations were systematically compared to identify structurally isomorphic combinations, and the experimentally observed arrangements within double and triple helices are among the most isomorphic. Unexpectedly, however, other combinations in the database are even more isomorphic, including several in which all-purine arrangements overlap with all-pyrimidine arrangements. These studies highlight some of the combinatoric and geometric versatility of base interactions and help provide a framework for analyzing and modeling isomorphic interactions and potentially for designing novel nucleic acid structures.

Base Composition↗

PubMed2003

Recognition of nucleic acid bases and base-pairs by hydrogen bonding to amino acid side-chains.

Sequence-specific protein-nucleic acid recognition is determined, in part, by hydrogen bonding interactions between amino acid side-chains and nucleotide bases. To examine the repertoire of possible interactions, we have calculated geometrically plausible arrangements in which amino acids hydrogen bond to unpaired bases, such as those found in RNA bulges and loops, or to the 53 possible RNA base-pairs. We find 32 possible interactions that involve two or more hydrogen bonds to the six unpaired bases (including protonated A and C), 17 of which have been observed. We find 186 "spanning" interactions to base-pairs in which the amino acid hydrogen bonds to both bases, in principle allowing particular base-pairs to be selectively targeted, and nine of these have been observed. Four calculated interactions span the Watson-Crick pairs and 15 span the G:U wobble pair, including two interesting arrangements with three hydrogen bonds to the Arg guanidinum group that have not yet been observed. The inherent donor-acceptor arrangements of the bases support many possible interactions to Asn (or Gln) and Ser (or Thr or Tyr), few interactions to Asp (or Glu) even though several already have been observed, and interactions to U (or T) only if the base is in an unpaired context, as also observed in several cases. This study highlights how complementary arrangements of donors and acceptors can contribute to base-specific recognition of RNA, predicts interactions not yet observed, and provides tools to analyze proposed contacts or design novel interactions.

Amino Acids↗

PubMedDate not supplied

Structure-based identification of small molecule binding sites using a free energy model.

We separately have shown that the maximal druglike affinity of a given binding site on a protein can be calculated on the basis of the binding-site structure alone by using a desolvation-based free energy model along with the notion that druglike ligands fall into certain physiochemical property ranges. Here, we present an approach where we reformulate the calculated druggability affinity as an additive free energy to facilitate the searching of whole protein surfaces for druglike binding sites. The highest-scoring patches in many cases represent known ligand-binding sites for druggable targets, but not for difficult targets. This approach differs from other approaches in that it does not simply identify pockets with the greatest volume but instead identifies pockets that are likely to be amenable to druglike small-molecule binding. Combining the method with a functional residue prediction method called SCA (statistical coupling analysis) results in the prediction of potentially druggable allosteric binding sites on p38alpha kinase.

Allosteric Site↗