JP2016527486A - 標的生体実体を標的にする生化学実体候補をスクリーニングする方法 - Google Patents
標的生体実体を標的にする生化学実体候補をスクリーニングする方法 Download PDFInfo
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Abstract
Description
本出願は、2013年6月13日に出願された米国仮特許出願第61/834,782号の利益を主張し、当該出願は、その全体が本明細書において参考として援用される。
参照による組込み
定義
序論
(i)候補生化学的実体の各々の10、20、30、40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300g/mol以内の分子量、
(ii)候補生化学的実体の各々の1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、22%、24%、26%、28%、30%、35%、40%、45%または50%以内の分子量、
(iii)候補生化学的実体の各々の原子数が1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、22、24、26、28、30、35、40、45、50、60、70、80、90、100、120、140、160、180、200、250、300、350、400、450、500、600、700、800、900または1000個以内の化学式、
(iv)候補生化学的実体の各々の間の1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、22、24、26、28、30、35、40、45、50、60、70、80、90、100、120、140、160、180、200、250、300、350、400、450、500、600、700、800、900または1000未満の全原子数の差、
(v)1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20未満の炭素原子数の差、
(vi)1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20未満の水素原子数の差、
(vii)1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20未満の窒素原子数の差、
(viii)1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20未満の酸素原子数の差、
(ix)1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20未満の硫黄原子数の差、
(x)候補生化学的実体の各々の1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、22%、24%、26%、28%、30%、35%、40%、45%または50%以内のlog Dで測定される極性、
(xi)候補生化学的実体の各々の1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、22%、24%、26%、28%、30%、35%、40%、45%または50%以内のlog P(分配係数)で測定される極性、
(xii)候補生化学的実体の各々の1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、22%、24%、26%、28%、30%、35%、40%、45%または50%以内のPSA(極性表面積)で測定される極性、
(xiii)同一の足場コア、
(xiv)グラフ理論で測定される化学的類似性、
(xv)0.5、0.6、0.7、0.75、0.8、0.81、0.82、0.83、0.84、0.85、0.86、0.87、0.88、0.89、0.9、0.91、0.92、0.93、0.94、0.95、0.96、0.97、0.98または0.99を超えるTanimoto(またはJaccard)係数T、
(xvi)1、2、3、4、5、6、7、8、9または10未満の芳香族基数の差、
(xvii)1、2、3、4、5、6、7、8、9または10未満の複素環基数の差、
(xviii)1、2、3、4、5、6、7、8、9または10未満の単環基数の差、
(xix)1、2、3、4、5、6、7、8、9または10未満の縮合環系数の差、
および(xx)1、2、3、4、5、6、7、8、9または10未満の二重結合数の差
が含まれる。
i)ベースラインと比較したシグネチャーの大きさの変化、
ii)ベースラインと比較したシグネチャーの方向の変化、および
iii)候補生化学的実体の接触の際のシグネチャーの単位時間あたりのシグナルの速度の変化
が含まれる。
i)第1の候補生化学的実体と接触する際のベースラインと比較したシグネチャーの大きさの変化は、第2の候補生化学的実体と接触する際のベースラインと比較したシグネチャーの大きさの変化の1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、22%、24%、26%、28%、30%、35%、40%、45%または50%以内であること、
ii)第1の候補生化学的実体と接触する際のベースラインと比較したシグネチャーの方向の変化は、第2の候補生化学的実体と接触する際のベースラインと比較したシグネチャーの方向の変化と同じであること、および
iii)第1の候補生化学的実体と接触する際のシグネチャーの単位時間あたりのシグナルの速度の変化は、第2の候補生化学的実体と接触する際のシグネチャーの単位時間あたりのシグナルの速度の変化の1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、22%、24%、26%、28%、30%、35%、40%、45%、50%、60%、70%、80%、90%、100%(1倍)、110%、120%、130%、140%、150%、160%、170%、180%、190%または200%(2倍)以内であること
が含まれる。
I.標的分子を標的にする薬物候補をスクリーニングする方法
A.同じまたは類似の足場を有する薬物候補
B.薬物候補の選択
1.直接比較
2.候補分子とのプレインキュベーション
3.参照分子とのプレインキュベーション
A.他のアッセイ
B.in vivoまたはin vitroの薬理特性
II.標的生体分子のための結合部分を同定する方法
III.構造−活性関係を判定する方法および/または生化学的実体を分類する方法
IV.追加の適用
V.シグネチャー
VI.標的生体分子および参照生化学的実体
本明細書に開示される方法のいずれかで使用するために、任意のRasタンパク質が企図される。3つのヒトras遺伝子は、H−RAS、N−RASおよびK−RAS4AおよびK−RAS4B(2つのK−RASタンパク質は選択的スプライシングから生じる)と呼ばれる、188から189個のアミノ酸の鎖で構成される極めて相同的なタンパク質をコードする。Rasサブファミリーの臨床的に最も注目すべきメンバーは、主に多くの種類のがんと結びつけられるために、H−RAS、K−RASおよび、N−RASであるが、このサブファミリーの多くの他のメンバーも同様にあり、例には、限定されないが、DIRAS1、DIRAS2、DIRAS3、ERAS、GEM、MRAS、NKIRAS1、NKIRAS2、NRAS、RALA、RALB、RAP1A、RAP1B、RAP2A、RAP2B、RAP2C、RASD1、RASD2、RASL10A、RASL10B、RASL11A、RASL11B、RASL12、REM1、REM2、RERG、RERGL、RRAD、RRASまたはRRAS2を含めることができる(その開示は参照により完全に組み込まれる、Wennerbergら、2005年、「The Ras superfamily at a glance」、J. Cell. Sci.118巻(Pt5):843〜6頁も参照)。Rasタンパク質の突然変異形も、開示の方法の範囲内での使用のために企図される。
VII.非線形活性部分
VIII.界面
IX.キット
X.系
ここで、本発明者らは、標的タンパク質のリアルタイムの立体配置変化の読み出しを使用する、リガンドスクリーニング方法としてのSHGの最初の使用を報告する。本発明者らは、タンパク質アルファシヌクレイン、パーキンソン病(PD)の治療標的、のスペルミンによって誘導される立体配置変化に重点を置いた。本発明者らは、ツール化合物としてスペルミンを使用して、タンパク質に結合してその立体配置をモジュレートするリガンドを同定することができるかどうか答えを求めた。アルファシヌクレインは140残基の非常に酸性のタンパク質であり、PDのための主要な標的である。PDはアルツハイマー病に次いで2番目に最も普通の神経変性疾患であり、米国では1,000,000〜1,500,000人に影響を及ぼす(Lang AE & Lozano AM、New England Journal of Medicine 339巻(16号):1130〜1143頁(1998年)。疾患の2つの特質は、中脳黒質中のドーパミン作動性ニューロンの減少、およびニューロン中の、主にアルファシヌクレインの凝集体で構成されるレーヴィ小体(LB)の存在である。アルファシヌクレインの点突然変異は早期発症PDの稀な形に関係があり、そのタンパク質が疾患機構に関係していることを示唆する(Klockgether T、Cell and Tissue Research318巻(1号):115〜120頁(2004年)。疾患患者の脳で見出されるより大きな凝集体の前に形成されるアルファシヌクレインのオリゴマーは、in vivoで神経毒である可能性を益々多くの証拠が示唆する(Winner Bら、Proceedings of the National Academy of Sciences. 108巻(10号):4194〜4199頁(2011年)。タンパク質がモノマーからフィブリル凝集体に進行する過程は、現在熱心な詳細調査の対象である(Norris EHら、Journal of Biological Chemistry280巻(22号):21212〜21219頁、2005年;Karpinar DPら、EMBO J28巻(20号):3256〜3268頁、2009年)。近年の報告は、タンパク質がin vivoでテトラマー構造を採用することを示し、モノマーへの解離がオリゴマー化および凝集に先行することを意味する。毒性の種に関係なく、モノマーのアルファシヌクレインは、それを安定させることができ、最も初期のステージで凝集を阻止することができる薬物のための魅力的な治療標的である。アルファシヌクレインは、in vitroで広く研究されている(Winner Bら、Proceedings of the National Academy of Sciences. 108巻(10号):4194〜4199頁、2011年;Bertoncini CWら、Proceedings of the National Academy of Sciences of the United States of America102巻(5号):1430〜1435頁、2005年;Conway KA、Harper JDおよびLansbury PT、Biochemistry39巻(10号):2552〜2563頁、2000年)。それは生来非構造化物であり、コンパクトなものから完全に伸長したものまで一定範囲の立体配置を採用する(Bertoncini CWら、Proceedings of the National Academy of Sciences of the United States of America102巻(5号):1430〜1435頁、2005年)。C末端とN末端の間の相互作用は、主にコンパクトな立体配置のタンパク質を安定させるようである。1つの仮説によると、タンパク質がスペルミンなどのポリアミンまたは低いpHに曝露されるとき、これらの相互作用が破壊され、in vitroで凝集速度は大いに増加する。スペルミンの効果についての別の仮説によると、結合したスペルミンはC末端領域の非常に負の電荷状態を低減し、タンパク質分子間の静電反発力を弱くし、凝集速度が大いに増強される(McClendon S、Rospigliosi CCおよびEliezer D、Protein Science18巻(7号):1531〜1540頁、2009年)。いずれの場合も、タンパク質は凝集の前に立体配置変化を受ける。
方法
結果
考察
(実施例2):アルファシヌクレインを標的にする薬物候補の差別的スクリーニング
この実施例では、SHGシグネチャーは、SHGベースラインと比較したSHGシグナルの大きさの変化(例えば、標的生化学的実体の立体配置状態のエンドポイント変化;あるいは、標的生化学的実体の立体配置状態の動態学的(リアルタイム)変化を測定することができる)、およびSHGベースラインと比較したSHGシグナルの方向の変化(SHGパラメータ)を測定することによって生じた。異なるものの、一部の場合には、1つまたは複数のSHG類似性パラメータを使用して、少なくとも5つの類似体のSHGシグネチャーのサブセットを互いに類似していると分類することができる(ペアでまたは全部)。例えば、SHGベースラインと比較したSHGシグナルの大きさの変化の差は、5つの類似体について互いの50%以内であり、SHGベースラインと比較したSHGシグナルの方向の変化の差は、ライブラリー中の全ての6つの生化学的実体について同じである。
(実施例3):アルファシヌクレインを標的にする承認薬のSHG検出
実験条件
結果
考察
(実施例4):構造−活性関係(SAR)の判定/カタログ作成
Claims (48)
- 生化学的実体をスクリーニングする方法であって、
(a)6つまたはそれを超える候補生化学的実体を含むライブラリーを用意するステップであり、前記6つまたはそれを超える候補生化学的実体は:
(i)前記候補生化学的実体の各々の150g/mol以内の分子量、
(ii)前記候補生化学的実体の各々の30%以内の分子量、
(iii)前記候補生化学的実体の各々の原子が15個以内の化学式、
(iv)前記候補生化学的実体の各々の間の15未満の全原子数の差、
(v)5未満の炭素原子数の差、
(vi)5未満の水素原子数の差、
(vii)5未満の窒素原子数の差、
(viii)5未満の酸素原子数の差、
(ix)5未満の硫黄原子数の差、
(x)前記候補生化学的実体の各々の10%以内のlog Dで測定される極性、
(xi)前記候補生化学的実体の各々の10%以内のlog P(分配係数)で測定される極性、
(xii)前記候補生化学的実体の各々の10%以内のPSA(極性表面積)で測定される極性、
(xiii)同一の足場コア、
(xiv)グラフ理論で測定される化学的類似性、
(xv)0.85を超えるTanimoto(またはJaccard)係数T、
(xvi)3未満の芳香族基数の差、
(xvii)3未満の複素環基数の差、
(xviii)3未満の単環基数の差、
(xix)3未満の縮合環系数の差、および
(xx)3未満の二重結合数の差
からなる群から選択される1つまたは複数の構造類似性パラメータを使用して判定するときに構造的に類似している、ステップと、
(b)標的生化学的実体の第1の立体配置状態を測定し、それによってベースラインを作成するステップと、
(c)前記候補生化学的実体の各々を同じ標的生化学的実体と接触させるステップと、
(d)前記標的生化学的実体の第2の立体配置状態を測定するステップと、
(e)前記第2の立体配置状態を使用して前記標的生化学的実体のシグネチャーを判定するステップと、
(f)前記シグネチャーに基づいて前記候補生化学的実体から1つまたは複数の生化学的実体を選択するステップと
を含む方法。 - 前記第1または第2の立体配置状態を測定するステップが、内部全反射(TIR)を使用する、請求項1に記載の方法。
- 前記第1または第2の立体配置状態を測定するステップが、第2高調波発生(SHG)を使用する、請求項1に記載の方法。
- 前記シグネチャーを判定するステップが、前記標的生化学的実体の立体配置状態の動態学的(リアルタイム)変化を測定するステップを含む、請求項1に記載の方法。
- 前記シグネチャーを判定するステップが、前記標的生化学的実体の立体配置状態のエンドポイント変化を測定するステップを含む、請求項1に記載の方法。
- 前記シグネチャーを判定するステップが、前記シグナルのシグナル強度を測定するステップを含む、請求項1に記載の方法。
- 前記シグネチャーを判定するステップが、前記ベースラインを使用する、請求項1に記載の方法。
- コンピュータ実行可能プログラムを使用して、1つまたは複数の構造類似性パラメータに基づいて前記6つまたはそれを超える候補生化学的実体を分析するステップをさらに含む、請求項1に記載の方法。
- コンピュータ実行可能プログラムを使用して、前記シグネチャーを分析するステップをさらに含む、請求項1に記載の方法。
- 前記候補生化学的実体の各々が、前記標的生化学的実体の立体配置状態において異なる変化を生成する、請求項1に記載の方法。
- 前記標的生化学的実体の立体配置状態の前記変化を、公知の立体配置モジュレーターによって生成される立体配置状態の変化と比較するステップをさらに含む、請求項1に記載の方法。
- 前記公知の立体配置モジュレーターが、公知の薬物である、請求項11に記載の方法。
- 前記公知の立体配置モジュレーターによって誘導される立体配置状態の前記変化に最も類似している立体配置状態の前記変化に基づいて、1つまたは複数の生化学的実体を選択するステップをさらに含む、請求項11に記載の方法。
- 前記公知の立体配置モジュレーターによって生成される立体配置状態の前記変化が、薬理特性または機能的効果に相関する、請求項11に記載の方法。
- ステップ(c)での接触の際に、前記候補生化学的実体の各々が異なるシグネチャーを生じる、請求項1に記載の方法。
- 前記候補生化学的実体の少なくとも2つが、類似の薬理特性または機能的効果を有する、請求項1に記載の方法。
- 前記候補生化学的実体の少なくとも2つが、類似の薬理特性または機能的効果を有しない、請求項1に記載の方法。
- i)前記ベースラインと比較した前記シグネチャーの大きさの変化、
ii)前記ベースラインと比較した前記シグネチャーの方向の変化、および
iii)前記候補生化学的実体の接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化
からなる群から選択されるシグネチャーパラメータを測定するステップをさらに含む、請求項1に記載の方法。 - i)第1の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの大きさの前記変化が、第2の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの大きさの前記変化の50%以内であること、
ii)前記第1の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの方向の前記変化が、前記第2の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの方向の前記変化と同じであること、および
iii)前記第1の候補生化学的実体との接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化が、前記第2の候補生化学的実体との接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化の2倍以内であること
からなる群から選択される1つまたは複数のシグネチャー類似性パラメータを使用して判定したときに、前記第1の候補生化学的実体によって生じる前記シグネチャーおよび前記第2の候補生化学的実体によって生じる前記シグネチャーが類似している、請求項1に記載の方法。 - 前記第1の立体配置状態が、前記標的生化学的実体を薬剤とインキュベートした後に測定される、請求項1に記載の方法。
- 前記薬剤が、前記ライブラリーからの候補生化学的実体である、請求項1に記載の方法。
- 1つまたは複数の生化学的実体が、前記シグネチャーと公知の薬理特性または公知の機能的効果との相関に基づいて選択される、請求項1に記載の方法。
- 生化学的実体をスクリーニングする方法であって、
(a)6つまたはそれを超える候補生化学的実体を含むライブラリーを用意するステップと、
(b)標的生化学的実体の第1の立体配置状態を測定し、それによってベースラインを作成するステップと、
(c)前記候補生化学的実体の各々を同じ標的生化学的実体と接触させるステップと、
(d)前記標的生化学的実体の第2の立体配置状態を測定するステップと、
(e)前記第2の立体配置状態を使用して少なくとも第1および第2の候補生化学的実体のシグネチャーを判定するステップと、
(f)前記第1の生化学的実体の前記シグネチャーを前記第2の生化学的実体の前記シグネチャーと比較するステップと、
(g)(f)での比較に基づいて、前記候補生化学的実体から1つまたは複数の生化学的実体を選択するステップと
を含む方法。 - 前記6つまたはそれを超える候補生化学的実体が、
(i)前記候補生化学的実体の各々の150g/mol以内の分子量、
(ii)前記候補生化学的実体の各々の30%以内の分子量、
(iii)前記候補生化学的実体の各々の原子が15個以内の化学式、
(iv)前記候補生化学的実体の各々の間の15未満の全原子数の差、
(v)5未満の炭素原子数の差、
(vi)5未満の水素原子数の差、
(vii)5未満の窒素原子数の差、
(viii)5未満の酸素原子数の差、
(ix)5未満の硫黄原子数の差、
(x)前記候補生化学的実体の各々の10%以内のlog Dで測定される極性、
(xi)前記候補生化学的実体の各々の10%以内のlog P(分配係数)で測定される極性、
(xii)前記候補生化学的実体の各々の10%以内のPSA(極性表面積)で測定される極性、
(xiii)同一の足場コア、
(xiv)グラフ理論で測定される化学的類似性、
(xv)0.85を超えるTanimoto(またはJaccard)係数T、
(xvi)3未満の芳香族基数の差、
(xvii)3未満の複素環基数の差、
(xviii)3未満の単環基数の差、
(xix)3未満の縮合環系数の差、および
(xx)3未満の二重結合数の差
からなる群から選択される1つまたは複数の構造類似性パラメータを使用して判定するときに構造的に類似している、請求項23に記載の方法。 - コンピュータ実行可能プログラムを使用して、前記シグネチャーを分析するステップをさらに含む、請求項23に記載の方法。
- 前記候補生化学的実体の各々が、前記標的生化学的実体の立体配置状態において異なる変化を生成する、請求項23に記載の方法。
- (c)での接触の際に、前記候補生化学的実体の各々が異なるシグネチャーを生じる、請求項23に記載の方法。
- 前記候補生化学的実体の少なくとも2つが、類似の薬理特性または機能的効果を有する、請求項23に記載の方法。
- i)前記ベースラインと比較した前記シグネチャーの大きさの変化、
ii)前記ベースラインと比較した前記シグネチャーの方向の変化、および
iii)前記候補生化学的実体の接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化
からなる群から選択されるパラメータを測定するステップをさらに含む、請求項23に記載の方法。 - i)第1の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの大きさの前記変化が、第2の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの大きさの前記変化の50%以内であること、
ii)前記第1の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの方向の前記変化が、前記第2の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの方向の前記変化と同じであること、および
iii)前記第1の候補生化学的実体との接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化が、前記第2の候補生化学的実体との接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化の2倍以内であること
からなる群から選択される1つまたは複数のシグネチャー類似性パラメータを使用して判定したときに、前記第1の候補生化学的実体によって生じる前記シグネチャーおよび前記第2の候補生化学的実体によって生じる前記シグネチャーが類似している、請求項23に記載の方法。 - 前記標的生化学的実体が、天然変性タンパク質である、請求項23に記載の方法。
- 前記天然変性タンパク質が、アルファシヌクレインである、請求項31に記載の方法。
- 前記標的生化学的実体が、公知の立体配置モジュレーターを有しない、請求項23に記載の方法。
- 前記生化学的実体の1つまたは複数の前記シグネチャーが、公知の薬理特性または公知の機能的効果と相関する、請求項23に記載の方法。
- 生化学的実体を分類する方法であって、
(a)生化学的実体のライブラリーを用意するステップであり、前記生化学的実体の各々は異なる分子構造を含む、ステップと、
(b)前記ライブラリー中の少なくとも1つの生化学的実体を同じ標的生化学的実体と接触させるステップと、
(c)前記標的生化学的実体の立体配置状態を測定するステップと、
(d)前記立体配置状態を使用してシグネチャーを判定するステップと、
(e)前記シグネチャーを使用して構造−活性関係(SAR)カタログを作成するステップと
含む方法。 - 前記SARを作成するステップが、前記シグネチャーを結合特性、機能的特性、効能、力価、選択性またはそれらの組合せと相関させるステップを含む、請求項35に記載の方法。
- 前記SARを作成するステップが、前記シグネチャーを前記候補生化学的実体の1つまたは複数の構造パラメータと相関させるステップを含み、前記構造パラメータは、分子量、化学式、全原子数、炭素原子数、水素原子数、窒素原子数、酸素原子数、硫黄原子数、log Dによって測定される極性、log Pによって測定される極性、PSA(極性表面積)によって測定される極性、足場コア、グラフ理論で測定される化学的類似性、Tanimoto(またはJaccard)係数T、芳香族基数、複素環基数、単環基数、縮合環系数および二重結合数からなる群から選択される、請求項35に記載の方法。
- 生化学的実体の前記ライブラリーが、薬物候補を含む、請求項35に記載の方法。
- 前記標的生化学的実体が、薬物標的である、請求項35に記載の方法。
- 薬理特性または機能的効果と関連する前記生化学的実体の少なくとも1つの中の結合部分を判定するために前記SARを分析するステップをさらに含む、請求項35に記載の方法。
- コンピュータ実行可能プログラムを使用して、前記シグネチャーを分析するステップをさらに含む、請求項35に記載の方法。
- 前記接触の前に前記標的生化学的実体の前記立体配置状態を測定し、それによってベースラインを作成するステップをさらに含む、請求項35に記載の方法。
- 前記シグネチャーが、前記標的生化学的実体の前記立体配置状態の変化を示す、請求項35に記載の方法。
- 前記シグネチャーを判定するステップが、前記標的生化学的実体の前記立体配置状態の動態学的(リアルタイム)変化を測定するステップを含む、請求項35に記載の方法。
- 前記シグネチャーを判定するステップが、前記標的生化学的実体の前記立体配置状態のエンドポイント変化を測定するステップを含む、請求項35に記載の方法。
- i)前記ベースラインと比較した前記シグネチャーの大きさの変化、
ii)前記ベースラインと比較した前記シグネチャーの方向の変化、および
iii)前記候補生化学的実体の接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化
からなる群から選択されるシグネチャーパラメータを測定するステップをさらに含む、請求項35に記載の方法。 - i)第1の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの大きさの前記変化が、第2の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの大きさの前記変化の50%以内であること、
ii)前記第1の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの方向の前記変化が、前記第2の候補生化学的実体との接触の際の前記ベースラインと比較した前記シグネチャーの方向の前記変化と同じであること、および
iii)前記第1の候補生化学的実体との接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化が、前記第2の候補生化学的実体との接触の際の前記シグネチャーの単位時間あたりのシグナルの速度の変化の2倍以内であること
からなる群から選択される1つまたは複数のシグネチャー類似性パラメータを使用して判定したときに、前記第1の候補生化学的実体によって生じる前記シグネチャーおよび前記第2の候補生化学的実体によって生じる前記シグネチャーが類似している、請求項35に記載の方法。 - 前記SARカタログまたは前記シグネチャーと、公知の薬理特性または公知の機能的効果との相関に基づいて、1つまたは複数の生化学的実体を選択するステップをさらに含む、請求項35に記載の方法。
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