Structural Classification of Complex Molecules by Artificial Intelligence Techniques

Structural Classification of Complex Molecules by Artificial Intelligence Techniques

Francisco Torrens (Universitat de València, Spain) and Gloria Castellano (Universidad Católica de Valencia San Vicente Mártir, Spain)
DOI: 10.4018/978-1-60960-860-6.ch002
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Algorithms for classification and taxonomy bases on criteria, e.g., information entropy. The feasibility of replacing a given molecule by similar ones in the composition of a complex drug is studied. Some local anaesthetics currently in use are classified using structural properties. In taxonomy the detailed comparison of the sequences of biomolecules, proteins or nucleic acids, allows the reconstruction of a molecular phylogenetic tree. The method is applied to the classifications of (1) indazolols (against Trichomonas vaginalis), (2) fullerenes and fullerite, (3) living and heat-inactivated lactic acid bacteria against cytokines, (4) phylogenesis of avian birds and 1918 influenza virus, (5) local anaesthetics, (6) transdermal-delivery percutaneous enhancers, (7) quantitative structure–activity relationship of anti-human immunodeficiency virus (HIV) compounds, (8) HIV inhibitors, e.g., thiocarbamates, N-aryloxazolidinone-5-carboxamides and styrylquinolines, (9) antimalarial aryltriazolylhydroxamates, (10) N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl) amines against prostate cancer, antimitotic 2-phenylindole-3-carbaldehydes against breast cancer and anti-tubulin agents against gastric cancer with indole ring. The entropy contributions may be studied with the equipartition conjecture. It is not within the scope of our simulation method to replace biological tests of drugs or field data in palaeontology, but such simulation methods can be useful to assert priorities in detailed experimental research. Available experimental and field data should be examined by different classification algorithms to reveal possible features of real biological significance.
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1. Introduction

Ab initio theoretical calculations, molecular dynamics simulations and docking studies are useful tools for investigating important biological complexes (Da Silva & Carvalho, 2005)(Da Silva, Ponte, Neto & Taft, 2005)(Da Silva, Almeida & Taft, 2004). At least three anti-human immunodeficiency virus type-1 (HIV-1) drugs, for combination therapy, became the standard treatment of acquired immunodeficiency syndrome (AIDS) drugs that have been licensed for clinical use, or are subjected to advanced clinical trials, belong to one of three classes: (1) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) {abacavir (ABC), emitricitabine [(–)FTC], zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC) and tenofovir disoproxil fumarate}, (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs) (emivirine, efavirenz, nevirapine and delavirdine) and (3) protease inhibitors (PIs) (lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir and indinavir) (Da Silva & Taft, 2005)(Da Silva & Taft, 2004)(Arissawa, Taft & Flecman, 2003). Various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (1) viral entry via blockade of viral coreceptors CXCR4 [bicyclam (AMD3100) derivatives] and CCR5 (TAK-799 derivatives), (2) viral adsorption via binding to viral envelope glycoprotein gp120 (polysulphates, polysulphonates, polycarboxylates, polyoxometalates, polynucleotides and negatively charged albumins), (3) viral assembly and disassembly via NCp7 Zn finger-targeted agents [2,2’-dithiobisbenzamides (DIBAs), azodicarbonamide (ADA)], (4) virus-cell fusion via binding to viral envelope glycoprotein gp41 (T-1249), (5) proviral deoxyribonucleic acid (DNA) integration via integrase inhibitors (4-aryl-2,4-dioxobutanoic acid derivatives) and (6) viral messenger ribonucleic acid (mRNA) transcription via inhibitors of transcription (transactivation) process (flavopiridol, fluoroquinolones) (Kuno, Palangsuntikul & Hannongbua, 2003)(Sharma, Kaushik, Singh, Kumar & Pandey, 2002)(De Clercq, 2002). New NRTIs, NNRTIs and PIs were developed that possess, respectively: (1) improved metabolic characteristics (phosphoramidate and cyclosaligenyl pronucleotides bypassing the first phosphorylation step of NRTIs), (2) increased activity [second or third generation NNRTIs (TMC-125, DPC-083)] and (3) different, non-peptidic scaffold [cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tripanavir)] (Kasai, Mizushina, Sugawara & Sakaguchi, 2002)(Painter, Andrews & Furman, 2000)(Mlinaric, Kreft, Umek & Strukelj, 2000).

The advent of so many new compounds, other than those that have been formally approved for the treatment of HIV infections, will undoubtedly improve the prognosis of patients with AIDS and AIDS-associated diseases. Nucleoside analogues constitute a family of biological molecules (ddI, d4T, ddC and 3TC), which play an important role in the transcription process of HIV. The normal nucleoside substrates, used by reverse transcriptase (RT) to synthesize DNA, are mimicked by the nucleoside analogues, which lacked a 3’-OH group and, consequently, act as chain terminators when incorporated into DNA by RT. Although the nucleoside analogues show good activity as inhibitors of HIV, their long-term usefulness is limited by toxicities. Resistance and mutation are also problems. The development of better drugs requires a better understanding of how the drugs work, the mechanism of drug resistance and interaction with receptor, and stability of the drugs inside active site. An HIV RT inhibitor ligand was proposed, which indicated highest docking scores and more hydrogen-bond interactions with the residues of RT active site (Da Silva, Carvalho & Taft, 2006).

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