A Fast Flexible Docking Method using an Incremental Construction Algorithm

Years of cumulative research can result in the development of a clinically useful drug, providing either a cure for a particular disease or symptomatic relief from a physiological disorder. A lead compound with a desired pharmacological activity may have associated with it undesirable side effects, characteristics that limit its bioavailability, or structural features which adversely influence its metabolism and excretion from the body. Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive.1 The prevalence of the use of bioisosteric replacements in drug design need not be emphasized. This topic has been reviewed in previous years.2-5 The objective of this review is to provide an overview of bioisosteres that incorporates sufficient detail to enable the reader to understand the concepts being delineated. While a few popular examples of the successful use of bioisosteres have been included, the George Patani graduated with a B.Pharm. in 1992 from the College of Pharmaceutical Sciences, Mangalore University at Manipal, India. In 1996, he received his M.S. in Pharmaceutical Science at Rutgers University under the direction of Professor Edmond J. LaVoie. He is presently pursuing graduate studies in pharmaceutics. His current research interests are focused on drug design and controlled drug delivery.

https://www.mch.estranky.sk/file/228/1996chemrev96-3147-76_bioisosterism.pdf

Bioisosterism: A Rational Approach in Drug Design.

The polyamine-biosynthetic pathway represents an inviting target for the development of agents inhibiting carcinogenesis and tumor growth. Polyamines play an essential role in the proliferation and development of mammalian cells. Deranged polyamine metabolism may be an important factor in carcinogenesis. Depletion of polyamines inhibits growth of neoplastic cells in vitro and in animal models. Several different classes of other anticancer agents may under some conditions exert enhanced effects when polyamine levels are depleted. Some suitable inhibitors of polyamine production are currently available and other promising compounds are presently being tested. It should soon prove possible to block polyamine biosynthesis at every step in the pathway. The use of these inhibitors alone and combined either with each other or with other antitumor agents will enable a full examination of the potential of this approach.

https://cancerres.aacrjournals.org/content/canres/48/4/759.full.pdf

Polyamine Metabolism and Its Importance in Neoplastic Growth and as a Target for Chemotherapy

Therapeutic oligonucleotide analogues which have improved nuclease resistance and improved cellular uptake are provided. Replacement of the normal phosphorodiester inter-sugar linkages found in natural oligomers with four atom linking groups forms unique di- and poly-nucleosides and nucleotides useful in regulating RNA expression and in therapeutics. Methods of synthesis and use are also disclosed.

Backbone modified oligonucleotide analogues

The new empirical rules for protein pKa predictions implemented in the PROPKA3.0 software package (Olsson et al. J. Chem. Theory Comput.2010, 7, 525–537) have been extended to the prediction of pKa shifts of active site residues and ionizable ligand groups in protein–ligand complexes. We present new algorithms that allow pKa shifts due to inductive (i.e., covalently coupled) intraligand interactions, as well as noncovalently coupled interligand interactions in multiligand complexes, to be included in the prediction. The number of different ligand chemical groups that are automatically recognized has been increased to 18, and the general implementation has been changed so that new functional groups can be added easily by the user, aided by a new and more general protonation scheme. Except for a few cases, the new algorithms in PROPKA3.1 are found to yield results similar to or better than those obtained with PROPKA2.0 (Bas et al. Proteins: Struct., Funct., Bioinf.2008, 73, 765–783). Finally, we present a n...

Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of pKa Values.

The present invention provides for the preparation and use of ribo- and deoxyribo-nucleosides and polynucleotide analogs. The polynucleotide analogs are made of polynucleosides which contain sulfonate and sulfonamide linkages.

Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages

2'-Deoxy-4'-thio-ribonucleosides, intermediates in their production, and their use as antiviral and anticancer agents are disclosed.

2'-deoxy-4'-thioribonucleosides and their antiviral activity

An inherited deficiency of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) produces selective lymphopenia and immunodeficiency disease in humans. Previous experiments have suggested that lymphospecific toxicity in this condition might result from the selective accumulation of toxic deoxyadenosine nucleotides by lymphocytes with high deoxycytidine kinase, levels and low deoxynucleotide dephosphorylating activity. The present experiments were designed to determine if deoxyadenosine analogs which are not substrates for adenosine deaminase might similarly be toxic toward lymphocytes and lymphoid tumors. Two such compounds, 2-chlorodeoxyadenosine and 2-fluorodeoxyadenosine, at concentrations of 3 nM and 0.15 microM, respectively, inhibited by 50% the growth of human CCRF-CEM malignant lymphoblasts in vitro. Each was phosphorylated in intact cells by deoxycytidine kinase accumulated as the nucleoside triphosphate, and inhibited DNA synthesis more than RNA synthesis. Both deoxynucleosides had significant chemotherapeutic activity against lymphoid leukemia L1210 in mice.

https://www.pnas.org/content/pnas/77/11/6865.full.pdf

Deoxycytidine kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo

2'-Deoxy-4'-thiocytidine (7 beta), 2'-deoxy-4'-thiouridine (9), and 4'-thiothymidine (10) have been synthesized and evaluated for cytotoxicity in vitro. All these compounds were cytotoxic to L1210, H-Ep-2, and CCRF-CEM cell lines. 4'-Thiothymidine was also active against herpes simplex 1 and human cytomegalovirus in cell culture.

Synthesis and biological activity of 2'-deoxy-4'-thio pyrimidine nucleosides.

The synthesis of 2-halo-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenines (4b and 4d) by coupling the 2,6-dihalopurine with 3-acetyl-5-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (2) followed by replacement of the 6-halogen with concomitant removal of the acyl blocking groups is described. 2-Fluoroadenine derivative 4g had to be prepared by the diazotization-fluorination of 2-aminoadenine nucleoside 4e. All three nucleosides provided good increases in life span of mice inoculated with P388 leukemia. The best results were obtained when the compounds were administered q3h x 8 on days 1, 5, and 9 after implantation of the leukemia cells. The 2',3'-dideoxynucleoside 5b, prepared by deacetylation of 4f and deoxygenation of the resultant 4h followed by removal of the benzoyl group of 5a, was slightly active against HIV in cell culture.

John A. Montgomery

Papers

Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages

2'-deoxy-4'-thioribonucleosides and their antiviral activity

Deoxycytidine kinase-mediated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo

Synthesis and biological activity of 2'-deoxy-4'-thio pyrimidine nucleosides.

Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine.